KR20120094711A - Biomarkers for diagnosing cardiac hypertrophy and method for diagnosis using the same - Google Patents

Abstract

The present invention relates to a biomarker for diagnosing myocardial hypertrophy and a method for diagnosing myocardial hypertrophy using the same. According to one embodiment, a biomarker for diagnosing myocardial hypertrophy, a diagnostic kit including the same, and a method for diagnosing myocardial hypertrophy using the same, may be useful for determining myocardial hypertrophy from biological samples, and as a tool for identifying the pathogenesis of myocardial hypertrophy. Can be used.

Description

Biomarker for diagnosing myocardial hypertrophy and method for diagnosing myocardial hypertrophy using the same {{Biomarkers for diagnosing cardiac hypertrophy and method for diagnosis using the same}

The present invention relates to a biomarker for diagnosing myocardial hypertrophy and a method for diagnosing myocardial hypertrophy using the same.

Heart disease is thought to be the leading cause of death worldwide. Heart disease is often caused by abnormalities in heart function, which often begins with myocardial hypertrophy, in which the size of heart cells increases, the sarcomeric organization and the synthesis of proteins increase. Myocardial hypertrophy can be caused by constant physical pressure or functional load caused by the heart being hypertensive, myocardial infarction, cardiac arrhythmia, abnormal endocrine system, and genetic factors. Hypertrophic reactions occur initially to increase heart function, but if myocardial hypertrophy persists, myocardial dysfunction may occur and myocardial infarction may die. Myocardial hypertrophy caused by various stimuli increases cell size, protein synthesis, and induces the expression of various genes.

Examples of substances that induce myocardial hypertrophy in the body include endothelin-1, angiotensin II, insulin-like growth factor-I. Endothelin-1 can transmit signals through the G protein-coupled receptor (GPCR), which binds to GPCR to activate phospholipase C, producing IP ₃ (inositol triphosphate), which is called endoplasmic reticulum or intracellular calcium storage. It activates the calcium channel in the store to release calcium from the myoplasmic reticulum, increasing the concentration of calcium in the cytoplasm. Increased calcium binds to calmodulin to dephosphorylate calcineurin and dephosphorylated calcineurin activates transcription factor NFAT to activate transcription of various myocardial hypertrophy related genes (FIG. 1).

Based on this, the present inventors can detect the myocardial hypertrophy by discovering proteins overexpressed or underexpressed by endothelin-1 by observing and analyzing changes in protein profiles in the HL-1 myocardial cell line by endothelin-1 using proteomics techniques. Biomarkers and methods of diagnosing myocardial hypertrophy have been established.

One embodiment provides a biomarker for diagnosing myocardial hypertrophy, a diagnostic kit including the same, and a method for diagnosing myocardial hypertrophy using the same.

One aspect provides a biomarker for diagnosing myocardial hypertrophy, comprising one or more proteins selected from the following group, wherein expression is relatively increased in cells that develop myocardial hypertrophy:

PDZ and LIM domain proteins having the amino acid sequence of SEQ ID NO: 1;

ADP-ribosylhydrolase having the amino acid sequence of SEQ ID NO: 2;

Peptidyl-prolyl cis-trans isomerase E having the amino acid sequence of SEQ ID NO: 3;

Translation elongation factor 1 delta isoform b of eukaryotic cells having the amino acid sequence of SEQ ID NO: 4;

Ran-specific GTPase-activating protein having the amino acid sequence of SEQ ID NO: 5;

ATP synthase subunit beta, mitochondrial precursor having the amino acid sequence of SEQ ID NO: 6; And

Isoform of Astrostatic Phosphoprotein PEA-15 Having the Amino Acid Sequence of SEQ ID NO: 7

Another aspect provides a biomarker for diagnosing myocardial hypertrophy, comprising one or more proteins selected from the following group, wherein expression is relatively reduced in cells with developing myocardial hypertrophy:

Isoform C protein of Lamin-A / C having the amino acid sequence of SEQ ID NO: 8;

A 75 kDa heat shock protein having the amino acid sequence of SEQ ID NO: 9;

Heat shock 70 kDa protein 14 having the amino acid sequence of SEQ ID NO: 10;

FK506-binding protein 4 having the amino acid sequence of SEQ ID NO: 11;

Poly (ADP-ribose) glycohydrolase ARH3 having the amino acid sequence of SEQ ID NO: 12;

Ubiquitin thioesterase protein OTUB1 having the amino acid sequence of SEQ ID NO: 13; And

Isoform short 14-3-3 protein β / α having the amino acid sequence of SEQ ID NO: 14.

According to one embodiment, the biomarker may include one or more proteins selected from the following group, and may include a biomarker for diagnosing myocardial hypertrophy in which expression is relatively increased in cells in which myocardial hypertrophy has developed.

PDZ and LIM domain proteins having a trypsin digested sequence of SEQ ID NOs: 15-21 and having a molecular weight of 34-37 kDa and a pi value of 6.3-6.5;

ADP-ribosylhydrolase having a trypsin digested sequence of SEQ ID NOs: 22 to 31 and having a molecular weight of 38 to 41 kDa and a pi value of 5.5 to 5.7;

Peptidyl-prolyl cis-trans isomerase E having a trypsin digested sequence of SEQ ID NOs: 32 to 39 and having a molecular weight of 32 to 35 kDa and a pi value of 5.3 to 5.5;

Translation elongation factor 1 delta isoform b of eukaryotic cells having a trypsin digested sequence of SEQ ID NOs: 40-47 and a molecular weight of 30-33 kDa and a pi value of 4.9-5.1;

Ran-specific GTPase-activating protein having a trypsin digested sequence of SEQ ID NOs: 48 to 50 and having a molecular weight of 22 to 25 kDa and a pi value of 5.4 to 5.6;

ATP synthase subunit beta, mitochondrial precursor, having a trypsin digested sequence of SEQ ID NOs: 51 and 52, having a molecular weight of 55 to 58 kDa and a pi value of 5.1 to 5.3; And

Isoform 1 of the astrogenic phosphoprotein PEA-15 having a trypsin digested sequence of SEQ ID NOs: 53-55 and having a molecular weight of 13-16 kDa and a pi value of 4.8-5.0.

According to one embodiment, the biomarker may include one or more proteins selected from the following group, and may include a biomarker for diagnosing myocardial hypertrophy in which expression is relatively reduced in cells in which myocardial hypertrophy has developed.

Isoform C protein of Lamin-A / C having a trypsin digested sequence of SEQ ID NOs: 56-61 and having a molecular weight of 64-67 kDa and a pi value of 6.3-6.5;

A 75 kDa heat shock protein having a trypsin digested sequence of SEQ ID NOs: 62 to 85 and having a molecular weight of 78 to 81 kDa and a pi value of 6.2 to 6.4;

Heat shock 70 kDa protein 14 having a trypsin digested sequence of SEQ ID NOs: 86-97 and having a molecular weight of 54-57 kDa and a pi value of 6.3-6.5;

FK506-binding protein 4 having a trypsin digested sequence of SEQ ID NOs: 98-100, having a molecular weight of 50-53 kDa and a pi value of 5.4-5.6;

Poly (ADP-ribose) glycohydrolase ARH3 having a trypsin digested sequence of SEQ ID NOs: 101 to 108 and having a molecular weight of 38 to 41 kDa and a pi value of 4.8 to 5.0;

Ubiquitin thioesterase protein OTUB1 having a trypsin digested sequence of SEQ ID NOs: 109-118 and having a molecular weight of 30-33 kDa and a pi value of 4.8-5.0; And

Isoform short 14-3-3 protein β / α having a trypsin digested sequence of SEQ ID NOs: 119 to 124 and a molecular weight of 26 to 29 kDa and a pi value of 4.7 to 4.9.

As used herein, the term “trypsin digested sequence” refers to the amino acid sequence of a polypeptide fragment produced by digesting the protein with trypsin for MALDI-TOF or MS / MS analysis. In addition, the molecular weight and pI are interpreted to include generally accepted experimental error ranges as values confirmed on two-dimentional electrophoresis.

Another aspect provides a myocardial hypertrophy diagnostic kit comprising an antibody that specifically binds to said protein or fragment of said protein.

A fragment of the protein can be, for example, an immunogenic fragment, which refers to a fragment of a biomarker protein having one or more epitopes that can be recognized by an antibody against a singular biomarker protein. According to one embodiment, the antibody may be a polyclonal antibody or a monoclonal antibody, but it is most preferred to use a monoclonal antibody.

The polyclonal antibody can be prepared by injecting a biomarker protein or fragment thereof as an immunogen into an external host according to conventional methods known to those skilled in the art. The external host can use mammals such as mice, rats, sheep, rabbits. The immunogen can be administered in combination with an adjuvant to increase antigenicity when injected by intramuscular, intraperitoneal or subcutaneous injection methods. Thereafter, blood may be collected periodically from an external host to collect serum showing enhanced titers and specificity for the antigen or to separate and purify the antibody therefrom.

The monoclonal antibodies can be prepared by the technology of generating immortalized cell lines by fusion known to those skilled in the art. Briefly, a method for producing a monoclonal antibody may be purified to immunize an appropriate amount (about 10 µg) in a Balb / C mouse or synthesize a polypeptide fragment of the protein and bind it to bovine serum albumin. After immunization, antigen-producing lymphocytes isolated from mice are fused with myeloma in humans or mice to produce immortalized hybridomas, and only the hybridoma cells that produce the desired monoclonal antibody are selected using the ELISA method. After propagation, monoclonal antibodies can be isolated and purified from the culture.

Myocardial hypertrophy diagnostic kit according to one embodiment may be prepared by conventional manufacturing methods known to those skilled in the art, and may typically include a freeze-dried form of the antibody and buffers, stabilizers, inert proteins and the like. The antibody can be labeled by radionuclides, fluorescors, enzymes, and the like.

Meanwhile, the monoclonal antibody according to one embodiment may be variously used in an immunoassay kit (eg, ELISA, antibody coated tube test, lateral-flow test, potable biosensor), and also has higher specificity and sensitivity. It can also be used to develop protein chips with various myocardial hypertrophy detection spectrum through the development of antibodies.

Another aspect is that the expression of one or more of the proteins having an amino acid sequence of SEQ ID NO: 1 to SEQ ID NO: 7 from the biological sample suspected of myocardial hypertrophy is increased relative to normal cardiomyocytes, or the SEQ ID NO: 8 to SEQ ID NO: Detecting whether expression of at least one of the proteins having an amino acid sequence of 14 is reduced relative to normal cardiomyocytes; And determining whether my biological sample is myocardial hypertrophy from the detection result.

Such biological samples include, but are not limited to, for example, proteome extracted from mammalian myocardial tissue, myocardial cells, myocardial tissue or cardiomyocytes. Biomarker proteins having the amino acid sequence of SEQ ID NO: 1 to SEQ ID NO: 14 are all mice ( Mus musculus ) and other mammals such as humans, monkeys, cows, horses, etc., the same protein is expressed, the homology (homology) is 90% or more database (http: //www.ncbi.nlm.nih. gov / blast). For example, PDZ and LIM domain proteins having the amino acid sequence of SEQ ID NO: 1 have 95% homology with human PDZ and LIM domain proteins. Therefore, it is apparent to those skilled in the art that the biomarker can be used for diagnosing myocardial hypertrophy of other mammals including humans.

In the diagnostic method, the detecting step is performed by performing two-dimensional electrophoresis on cardiomyocytes and normal cardiomyocytes suspected of myocardial hypertrophy to confirm the expression level of the biomarker protein, or cardiomyocytes suspected of myocardial hypertrophy. Contacting with a kit comprising an antibody according to one embodiment may comprise confirming the presence of the biomarker protein via an antigen antibody reaction. For example, when using two-dimensional electrophoresis, the proteome of normal cardiomyocytes and cardiomyocytes of a suspected myocardial hypertrophy patient is extracted, and the proteome is profiled by two-dimensional electrophoresis, from which the expression of the biomarker protein is expressed. If this increase or decrease is confirmed, it can be judged as myocardial hypertrophy. On the other hand, immunoassays currently well known as antigen antibody reactions include, for example, enzyme immunoassay (ELISA, Coated tube), a method using magnetic particles bound to antibodies, and a method using latex particles bound to antibodies.

According to one embodiment, a biomarker for diagnosing myocardial hypertrophy, a diagnostic kit including the same, and a method for diagnosing myocardial hypertrophy using the same, may be useful for determining myocardial hypertrophy from biological samples, and as a tool for identifying the pathogenesis of myocardial hypertrophy. Can be used.

Figure 1 shows the intracellular signal transduction pathway of endothelin-1 inducing myocardial hypertrophy.
Figure 2a shows the increase in the nucleus of ANF protein when treated with cells endothelin-1. CON refers to the control group, ET-1 refers to the experimental group treated with endothelin-1.
Figure 2b shows the mRNA transcription level of ANF in cells after treatment with endothelin-1 using RT-PCR.
Figure 3 separates the cell reactants in the case of not treated with endothelin-1 (A) and treated (B) using two-dimensional electrophoresis and displays differently expressed spots.
Figure 4a is a graph showing the difference in the expression amount of each spot differentially expressed in FIG.
4B is a functional classification of proteins identified using a mass spectrometer.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example  1: Identification of Induction of Myocardial Hypertrophy by Endothelin-1 in Myocardial Cell Line

Myocardial cell line HL-1 (Claycomb et al., Proc . Natl . Acad . Sci . USA 1998, 95, 2979-2984) was prepared in 10% FBS (Sigma), 0.1 mM norepinephrin (Sigma), in Claycomb medium (Sigma), 100 units / ml penicillin, 100 µg / ml streptomycin (Gibco / BRL) and 2 mM L-glutamine (Life Technologies) were added and cultured daily at 37 ° C., 5% CO ₂ . Incubate 2 x 10 ⁶ cells in 100 mm Petri dishes coated with 0.02% gelatin / 0.00125% fibronectin (Sigma), and stop cell growth in serum-free DMEM medium for 4 hours later. , 100 nM of endothelin-1 (Calbiochem) was added and left for 48 hours. Cells were then fixed, treated with anti-trial natriuretic factor antibody (Bachem), and then incubated with Alexa 546 labeled secondary mouse antibody (red) (Bachem). The cells were stained with DAPI (Invitrogen), and the images were collected using a confocal microscope (Zeiss).

From the results of FIG. 2A, it was confirmed that when endothelin-1 was treated, ANF protein in the nucleus was increased, and thus a signal inducing myocardial hypertrophy was transmitted by endothelin-1.

The myocardial cell line HL-1 cultured as above was treated with 100 nM endothelin-1 for 24 hours. Then, total RNA was isolated using RNeasy mini kit (Qiagen), and then 1 μg of total RNA was used as a template, and c-DNA synthesis was performed using M-MLV Reverse Transcriptase (Bioneer) to encode ANF protein. In this case, a primer (5'-GGCTCCTTCTCCATCACCCTG-3 ', SEQ ID NO: 125) and a reverse primer (5'-TCTTCGGTACCGGAAGCTGTT-3', SEQ ID NO: 126) were used. PCR was first performed with predenature for 4 minutes at 94 ° C, denature for 1 minute at 94 ° C, annealing for 1 minute at 53 ° C, and elongation for 1 minute at 72 ° C, followed by 10 cycles at 72 ° C. During post-elongation.

Figure 2b shows the results of the synthesis of cDNA encoding the ANF protein. When endothelin-1 was treated, it was found that the transcription of gene encoding ANF, a marker of myocardial hypertrophy, was increased. From this, it was confirmed that endothelin-1 induced myocardial hypertrophy.

Example  2: Identification of Proteins by Two-Dimensional Electrophoresis and Differential Expression of Myocardial Hypertrophy

After washing the endothelin-1 treated myocardial cell line HL-1 three times with cold PBS as in Example 1, lysis buffer (2 M urea, 2 M thiourea, 5% CHAPS, 50 mM DTT, 0.5% IPG buffer) The cells were added to a protease inhibitor cocktail, and then ultrasonically crushed. Thereafter, the mixture was shaken at room temperature for 1 hour, and the supernatant was recovered by centrifugation at 12,000 rpm for 15 minutes.

Rehydrate IPG strips (pH 4-7, 13 cm, linear; GE Healthcare) overnight with rehydration solution (8M urea, 2% CHAPS, 0.5% IPG buffer (pH 4-7), 18 mM DTT, bromophenol blue) rehydration). Then, using the Isoelectric focusing system (GE Healthcare), 100 V (3 hours), 500 V (1 hour), 1000 V (1 hour), 2500 V (1 hour), 8000 V (30 minutes) with a linear gradient, Then it was separated at 8000 V until 100,000 Vh was reached. After isoelectric focusing, the IPG strips were soaked in equilibration buffer (6M urea, 2% SDS, 75 mM Tris / HCl [pH 8.8], 29.3% glycerol, 0.01% DTT, 0.02% bromophenol blue) and then 15 minutes at 25 ° C. Shook for a while. After equilibration, the IPG strips are placed on a 10% polyacrylamide gel (25 x 35 cm), sealed with 0.5% agarose solution, and then electrophoresis buffer (24 mM Tris, 192 mM) in SE 600 Ruby electrophoresis system (GE Healthcare). glycine, 0.1% SDS) was added for 10 minutes at 10 mA, and then electrophoresis was performed under conditions of 30 mA until bromophenol blue was 0.5 cm from the bottom of the gel.

Thereafter, the separated gel was stained with a silver staining kit (GE Healthcare). The silver dyeing process is as follows. After fixing for more than 2 hours to a solution consisting of 50% methanol, 12% acetic acid, 0.05% formaldehyde, washed three times for 20 minutes with 50% ethanol, and then for 1 minute with 0.2% Sodium thiosulfate solution Sensitizing. Thereafter, the mixture was washed with distilled water, and then reacted with 0.1% silver nitrate, 0.075% formaldehyde (37%) solution for 20 minutes, washed again with distilled water, and then pre-cold 6% sodium carbonate, 0.075% formaldehyde (37%). After reacting with the solution for about 7 minutes, the solution was visualized (developing), and then the reaction was stopped by treating with 50% methanol and 12% acetic acid solution. Thereafter, the silver stained gel was scanned with an image scanner (GE Healthcare). Images of endothelin-1 treated gels were analyzed using Progenesis Workstation Software (Nonlinear Dynamics). Compared to the control and endothelin-1 treated gels, the spots that were consistently changed from each of the three gels were selected as differentially expressed proteins.

The results are shown in FIG. 3, and differently expressed spots are indicated by red circles.

Example  3: Identification and analysis of differentially expressed proteins

The spots selected as differentially expressed in Example 2 were cut out from the gel, destained for 5 minutes with a solution of 30 mM potassium ferricyanide and 100 mM sodium thiosulfate in a 1: 1 mixture, and then distilled water four times for 5 minutes. Washed. The washed gel pieces were incubated in 200 mM ammonium bicarbonate solution at 37 ° C. for 30 minutes and then dehydrated twice with acetonitrile for 10 minutes. The dehydrated gel pieces were rehydrated with 10 ng / ul trypsin dissolved in 25 mM ammonium bicarbonate, which was incubated overnight at 37 ° C. to decompose into peptides. 0.1% trifluoroacetic acid dissolved in 60% acetonitril was incubated three times for 10 minutes to recover the cleaved peptides in a new tube. Finally, gel fragments were dehydrated using acetonitril and then recovered in a new tube. The collected supernatant was dried using a vacuum centrifuge.

After dissolving the dried sample in 0.4% acetic acid, peptides were separated for 40 minutes with a gradient of 5-40% acetonitril using an Agilent Seires 1200LC system (Agilent Technologies) and then for 10 minutes with a 40-80% acetonitril gradient. LTQ electrospray ionization linear single quadrupole ion-trap mass spectrometer (Thermo) was used.

All MS / MS spectra were tested using the International Protein Index mouse protein sequence database (IPI, version 3.24, European Bioinformatic Institute) using the SEQUEST search engine. The peptide mass tolerance was 3.0 Da, the fragment ion mass tolerance was 1.0 Da and the methionine oxidation. The parameters of the modification were set as conditions.

The protein searched by the above method is shown in Table 1 below. Shown together. In addition, the amino acid sequence and position of the polypeptide fragment identified from the searched protein are shown in Table 2.

Spot No. Protein name Accession No. MW (Da) pI Matched peptide Coverage (%) Fold change One Isoform C of Lamin-A / C
(SEQ ID NO: 8) P48678_2 65446 6.4 6 14 -5.08 2 Heat shock protein 75 kDa
(SEQ ID NO: 9) Q9CQN1 80209 6.3 30 50 -2.18 3 Heat shock 70 kDa protein 14
(SEQ ID NO: 10) Q99M31 55883 6.4 26 35 -1.03 4 FK506-binding protein 4
(SEQ ID NO: 11) P30416 51441 5.5 4 11 -2.74 5 PDZ and LIM domain protein 1
(SEQ ID NO: 1) O70400 35643 6.4 17 45 2.37 6 ADP-ribosylhydrolase
(SEQ ID NO: 2) Q8BGK2 39885 5.6 16 35 0.42 7 Peptidyl-prolyl cis-trans isomerase (SEQ ID NO: 3) Q9QZH3 33449 5.4 20 41 0.99 8 Eukaryotic translation elongation factor 1 delta isoform b (SEQ ID NO: 4) Q80T06 31292 5.0 6 24 1.34 9 Ran-specific GTPase-activating protein (SEQ ID NO: 5) P34022 23596 5.5 4 28 0.65 10 ATP synthase subunit beta, mitochondrial precursor
(SEQ ID NO: 6) P56480 56300 5.2 18 31 1.77 11 Poly (ADP-ribose) glycohydrolase ARH3
(SEQ ID NO: 12) Q8CG72 39414 4.9 17 36 0.8 12 Ubiquitin thioesterase protein OTUB1 (SEQ ID NO: 13) Q7TQI3 31270 4.9 58 63 -1.18 13 Isoform Short 14-3-3 protein β / γ (SEQ ID NO: 14) Q9CQV8_2 27854 4.8 7 32 -0.28 14 Isoform 1 of Astrocytic phosphoprotein PEA-15
(SEQ ID NO: 7) Q62048_1 15054 4.9 9 37 0.94

Spot
No. Protein Name Position Mass Identified Peptides One

Isoform C of Lamin-A / C

29-41 1628.80 LQEKEDLQELNDR (SEQ ID NO 56) 79-89 1164.54 AAYEAELGDAR (SEQ ID NO 57) 145-155 1118.58 EAALSTALSEK (SEQ ID NO 58) 281-296 1751.86 NSNLVGAAHEELQQSR (SEQ ID NO: 59) 299-311 1429.78 IDSLSAQLSQLQK (SEQ ID NO: 60) 528-541 1490.74 TALINSTGEEVAMR (SEQ ID NO: 61) 2


























Heat shock protein 75 kDa


























61-84 2643.26 STQAAEDKEEESLHSIISNTEAVR (SEQ ID NO 62) 98-105 926.59 KLLDIVAR (SEQ ID NO 63) 117-128 1288.65 ELISNASDALEK (SEQ ID NO: 64) 153-179 2845.49 KGTITIQDTGIGMTQEELVSNLGTIAR (SEQ ID NO: 65) 184-198 1635.81 AFLEALQNQAETSSK (SEQ ID NO: 66) 223-254 3249.56 SAAPESPGYQWLSDGSGVFEIAEASGVRPGTK (SEQ ID NO 67) 279-292 1647.83 YSNFVSFPLYLNGK (SEQ ID NO: 68) 294-306 1559.78 INTLQAIWMMDPK (SEQ ID NO: 69) 307-318 1598.70 DISEFQHEEFYR (SEQ ID NO: 70) 343-359 2031.98 SIFYVPEMKPSMFDVSR (SEQ ID NO 71) 360-370 1180.61 ELGSSVALYSR (SEQ ID NO 72) 391-404 1512.78 GVVDSEDIPLNLSR (SEQ ID NO: 73) 405-414 1170.66 ELLQESALIR (SEQ ID NO 74) 427-433 883.44 FFIDQSK (SEQ ID NO: 75) 442-451 1323.60 FFEDYGLFMR (SEQ ID NO 76) 452-468 1858.95 EGIVTTAEQDIKEDIAK (SEQ ID NO 77) 472-491 2125.03 YESSALPAGQLTSLPDYASR (SEQ ID NO: 78) 508-520 1574.72 HLAEHSPYYEAMK (SEQ ID NO 79) 549-565 2016.04 LISVETDIVVDHYKEEK (SEQ ID NO: 80) 576-589 1737.81 LSEKETEDLMAWMR (SEQ ID NO: 81) 596-604 1062.62 VTNVKVTFR (SEQ ID NO: 82) 605-621 1810.91 LDTHPAMVTVLEMGAAR (SEQ ID NO: 83) 637-649 1491.84 AQLLQPTLEINPR (SEQ ID NO 84) 680-689 1025.55 IAAGLVDDPR (SEQ ID NO 85) 3














Heat shock 70 kDa protein 14













34-44 1204.65 VTPAIVAYSER (SEQ ID NO: 86) 98-109 1452.71 LRYEIDTGEETK (SEQ ID NO 87) 110-118 1011.53 LVNPEDVAR (SEQ ID NO: 88) 153-168 1502.78 SALGEAAGAAGFNVLR (SEQ ID NO 89) 169-190 2287.20 LIHEPSAALLAYGIGQDHPTGK (SEQ ID NO: 90) 191-197 805.47 SNVLVFK (SEQ ID NO: 91) 198-216 1999.97 LGGTSLSLSVMEVNSGMYR (SEQ ID NO: 92) 217-245 3155.52 VLSTNTSDNIGGAHFTDTLAQYLASEFQR (SEQ ID NO: 93) 321-331 1208.57 QTGFTADDINK (SEQ ID NO 94) 403-425 2388.21 GVDESGADRFTVLFPSGTPLPAR (SEQ ID NO 95) 458-469 1402.78 FAQVVLQDLDKK (SEQ ID NO 96) 475-483 1002.58 DILAVLTMK (SEQ ID NO: 97) 4 FK506-binding protein 4 7-27 2063.05 AAENGAQSAPLPLEGVDISPK (SEQ ID NO: 98) 138-151 1531.70 GEDLTEEEDGGIIR (SEQ ID NO: 99) 358-372 1682.85 RGEAHLAVNDFDLAR (SEQ ID NO: 100) 5








PDZ and LIM domain protein 1







17-31 1628.89 LVGGKDFEQPLAISR (SEQ ID NO: 15) 87-98 1413.76 IWSPLVTEEGKR (SEQ ID NO: 16) 103-121 2102.03 MNLASEPQEVLHIGSAHNR (SEQ ID NO: 17) 122-135 1419.68 SAMPFTASPAPSTR (SEQ ID NO: 18) 136-163 3089.46 VITNQYNSPTGLYSSENISNFNNAVESK (SEQ ID NO: 19) 164-195 3396.68 TSASGEEANSRPVVQPHPSGSLIIDKDSEVYK (SEQ ID NO: 20) 209-235 2948.49 QSTSFLVLQEILESDGKGDPNKPSGFR (SEQ ID NO: 21) 6









ADP-ribosylhydrolase









25-38 1572.80 ENSVLGSIQEELQK (SEQ ID NO: 22) 39-51 1270.69 TGGLDSLVLSPGR (SEQ ID NO: 23) 52-61 1198.54 WPVSDNTIMH (SEQ ID NO: 24) 86-101 1857.87 YVETVETLSEHRPDPS (SEQ ID NO: 25) 187-193 854.48 PLVQWGR (SEQ ID NO 26) 212-226 2014.87 HMAEYQEHWFYFEAK (SEQ ID NO 27) 227-234 1169.55 WQFYLEER (SEQ ID NO 28) 236-255 2411.09 IREDAEDKVTFPDNYDAEER (SEQ ID NO 29) 327-335 1115.56 GLYQELEHK (SEQ ID NO: 30) 336-347 1306.71 GRLEDLGAALHR (SEQ ID NO 31) 7








Peptidyl-prolyl cis-trans isomerase E








6-20 1661.86 RVLYVGGLAEEVDDK (SEQ ID NO: 32) 21-45 2844.46 VLHAAFIPFGDITDIQIPLDYETEK (SEQ ID NO: 33) 94-104 1387.68 PVWSDDDWLKK (SEQ ID NO 34) 109-134 2836.33 TLEENKEEEGPEPPKAEAQEGEPTAK (SEQ ID NO: 35) 138-147 1193.58 SNPQVYMDIK (SEQ ID NO: 36) 162-173 1364.64 SDVVPMTAENFR (SEQ ID NO 37) 218-227 1267.64 KFDDENFILK (SEQ ID NO: 38) 262-276 1668.88 HVVFGEVTEGLDVLR (SEQ ID NO 39) 8








Eukaryotic translation elongation factor 1 delta isoform b






6-20 1661.86 RVLYVGGLAEEVDDK (SEQ ID NO: 40) 21-45 2844.46 VLHAAFIPFGDITDIQIPLDYETEK (SEQ ID NO: 41) 94-103 1259.58 PVWSDDDWLK (SEQ ID NO 42) 109-134 2836.33 TLEENKEEEGPEPPKAEAQEGEPTAK (SEQ ID NO: 43) 138-147 1193.58 SNPQVYMDIK (SEQ ID NO: 44) 162-173 1364.64 SDVVPMTAENFR (SEQ ID NO 45) 218-227 1267.64 KFDDENFILK (SEQ ID NO 46) 262-276 1668.88 HVVFGEVTEGLDVLR (SEQ ID NO 47) 9
Ran-specific GTPase-activating protein
6-39 3888.68 DSHEDHDTSTENADESNHDPQFEPIVSLPEQEIK (SEQ ID NO 48) 40-50 1380.63 TLEEDEEELFK (SEQ ID NO 49) 58-68 1334.61 FASENDLPEWK (SEQ ID NO 50) 10 ATP synthase subunit beta, mitochondrial precursor 42-53 1274.64 ELISNASDALDK (SEQ ID NO: 51) 73-82 1193.64 IDIIPNPQER (SEQ ID NO 52) 11










Poly (ADP-ribose) glycohydrolase ARH3










57-75 1946.97 VLSHVESLEPDPGTPGSAR (SEQ ID NO: 101) 76-89 1679.73 TETLYYTDDTAMTR (SEQ ID NO: 102) 90-109 2242.14 ALVQSLLAKEAFDEVDMAHR (SEQ ID NO: 103) 121-131 1110.61 GYGAGVITVFK (SEQ ID NO: 104) 163-178 1663.88 VAGISLAYSSVQDVQK (SEQ ID NO: 105) 240-251 1452.67 ELGMEERPYSSR (SEQ ID NO: 106) 252-266 1697.97 LKKVGELLDQDVVSR (SEQ ID NO: 107) 285-309 2952.41 TAIYCFLRCMEPHPEIPSTFNSLQR (SEQ ID NO: 108) 12

















Ubiquitin thioesterase protein OTUB1
















37-51 1722.93 IQQEIAVQNPLVSER (SEQ ID NO: 109) 52-59 963.56 LELSVLYK (SEQ ID NO: 110) 60-71 1514.65 EYAEDDNIYQQK (SEQ ID NO: 111) 95-113 2175.10 AFGFSHLEALLDDSKELQR (SEQ ID NO: 112) 121-151 3675.73 SKEDLVSQGFTEFTIEDFHNTFMDLIEQVEK (SEQ ID NO: 113) 177-185 1049.59 LLTSGYLQR (SEQ ID NO: 114) 186-198 1581.76 ESKFFEHFIEGGR (SEQ ID NO: 115) 228-238 1325.63 SVSIQVEYMDR (SEQ ID NO: 116) 239-256 1838.84 GEGGTTNPHVFPEGSEPK (SEQ ID NO: 117) 257-271 1912.02 VYLLYRPGHYDILYK (SEQ ID NO: 118) 13




Isoform Short 14-3-3 protein β / γ




42-49 906.52 NLLSVAYK (SEQ ID NO: 119) 104-115 1349.72 YLILNATQAESK (SEQ ID NO: 120) 128-138 1195.57 YLSEVASGENK (SEQ ID NO: 121) 138-157 2286.11 KQTTVSNSQQAYQEAFEISK (SEQ ID NO: 122) 194-212 2158.00 TAFDEAIAELDTLNEESYK (SEQ ID NO: 123) 213-222 1188.65 DSTLIMQLLR (SEQ ID NO: 124) 14

Isoform 1 of Astrocytic phosphoprotein PEA-15
36-54 2169.00 SEEITTGSAWFSFLESHNK (SEQ ID NO 53) 55-71 2091.06 LDKDNLSYIEHIFEISR (SEQ ID NO 54) 72-83 1476.78 RPDLLTMVVDYR (SEQ ID NO: 55)

<110> Korea Institute of Science and Technology <120> Biomarker for diagnosing cardiac hypertrophy and method for          diagnosis using the same <160> 126 <170> Kopatentin 1.71 <210> 1 <211> 327 <212> PRT <213> Mus musculus <400> 1 Met Thr Thr Gln Gln Ile Val Leu Gln Gly Pro Gly Pro Trp Gly Phe   1 5 10 15 Arg Leu Val Gly Gly Lys Asp Phe Glu Gln Pro Leu Ala Ile Ser Arg              20 25 30 Val Thr Pro Gly Ser Lys Ala Ala Ile Ala Asn Leu Cys Ile Gly Asp          35 40 45 Leu Ile Thr Ala Ile Asp Gly Glu Asp Thr Ser Ser Met Thr His Leu      50 55 60 Glu Ala Gln Asn Lys Ile Lys Gly Cys Ala Asp Asn Met Thr Leu Thr  65 70 75 80 Val Ser Arg Ser Glu Gln Lys Ile Trp Ser Pro Leu Val Thr Glu Glu                  85 90 95 Gly Lys Arg His Pro Tyr Lys Met Asn Leu Ala Ser Glu Pro Gln Glu             100 105 110 Val Leu His Ile Gly Ser Ala His Asn Arg Ser Ala Met Pro Phe Thr         115 120 125 Ala Ser Pro Ala Pro Ser Thr Arg Val Ile Thr Asn Gln Tyr Asn Ser     130 135 140 Pro Thr Gly Leu Tyr Ser Ser Glu Asn Ile Ser Asn Phe Asn Asn Ala 145 150 155 160 Val Glu Ser Lys Thr Ser Ala Ser Gly Glu Glu Ala Asn Ser Arg Pro                 165 170 175 Val Val Gln Pro His Pro Ser Gly Ser Leu Ile Ile Asp Lys Asp Ser             180 185 190 Glu Val Tyr Lys Met Leu Gln Glu Lys Gln Glu Leu Asn Glu Pro Pro         195 200 205 Lys Gln Ser Thr Ser Phe Leu Val Leu Gln Glu Ile Leu Glu Ser Asp     210 215 220 Gly Lys Gly Asp Pro Asn Lys Pro Ser Gly Phe Arg Ser Val Lys Ala 225 230 235 240 Pro Val Thr Lys Val Ala Ala Ser Val Gly Asn Ala Gln Lys Leu Pro                 245 250 255 Ile Cys Asp Lys Cys Gly Thr Gly Ile Val Gly Val Phe Val Lys Leu             260 265 270 Arg Asp His His Arg His Pro Glu Cys Tyr Val Cys Thr Asp Cys Gly         275 280 285 Ile Asn Leu Lys Gln Lys Gly His Phe Phe Val Glu Asp Gln Ile Tyr     290 295 300 Cys Glu Lys His Ala Arg Glu Arg Val Thr Pro Pro Glu Gly Tyr Asp 305 310 315 320 Val Val Thr Val Phe Arg Glu                 325 <210> 2 <211> 353 <212> PRT <213> Mus musculus <400> 2 Met Glu Lys Phe Lys Ala Ala Met Leu Leu Gly Ser Val Gly Asp Ala   1 5 10 15 Leu Gly Tyr Gly Asn Ile Cys Arg Glu Asn Ser Val Leu Gly Ser Ile              20 25 30 Gln Glu Glu Leu Gln Lys Thr Gly Gly Leu Asp Ser Leu Val Leu Ser          35 40 45 Pro Gly Arg Trp Pro Val Ser Asp Asn Thr Ile Met His Met Ala Thr      50 55 60 Ala Glu Ala Leu Thr Thr Asp Tyr Trp Cys Leu Asp Asp Leu Tyr Arg  65 70 75 80 Glu Met Val Lys Arg Tyr Val Glu Thr Val Glu Thr Leu Ser Glu His                  85 90 95 Arg Pro Asp Pro Ser Thr Ile Glu Gly Cys Ser Gln Leu Lys Pro Asp             100 105 110 Asn Tyr Leu Leu Ala Trp His Thr Pro Phe Ser Glu Lys Gly Ser Gly         115 120 125 Phe Gly Ala Ala Thr Lys Ala Met Cys Ile Gly Met Arg Tyr Trp Lys     130 135 140 Pro Glu Arg Leu Glu Thr Leu Ile Glu Val Ser Ile Glu Cys Gly Arg 145 150 155 160 Met Thr His Asn His Pro Thr Gly Phe Leu Gly Ser Leu Cys Thr Ala                 165 170 175 Leu Phe Ala Ser Tyr Ala Leu Gln Gly Lys Pro Leu Val Gln Trp Gly             180 185 190 Arg Glu Met Leu Lys Val Leu Pro Leu Ala Glu Glu Tyr Cys Arg Lys         195 200 205 Thr Ile Arg His Met Ala Glu Tyr Gln Glu His Trp Phe Tyr Phe Glu     210 215 220 Ala Lys Trp Gln Phe Tyr Leu Glu Glu Arg Lys Ile Arg Glu Asp Ala 225 230 235 240 Glu Asp Lys Val Thr Phe Pro Asp Asn Tyr Asp Ala Glu Glu Arg Asp                 245 250 255 Lys Thr Tyr Lys Lys Trp Ser Ser Glu Gly Arg Gly Gly Arg Arg Gly             260 265 270 His Asp Ala Pro Met Ile Ala Tyr Asp Ala Leu Leu Ala Ser Gly Ser         275 280 285 Asn Trp Thr Glu Leu Cys Gln Arg Ala Met Phe His Gly Gly Glu Ser     290 295 300 Gly Ala Thr Gly Thr Ile Ala Gly Cys Leu Phe Gly Leu Leu His Gly 305 310 315 320 Leu Ala Thr Val Pro Arg Gly Leu Tyr Gln Glu Leu Glu His Lys Gly                 325 330 335 Arg Leu Glu Asp Leu Gly Ala Ala Leu His Arg Leu Ser Thr Glu Glu             340 345 350 Lys     <210> 3 <211> 301 <212> PRT <213> Mus musculus <400> 3 Met Ala Thr Thr Lys Arg Val Leu Tyr Val Gly Gly Leu Ala Glu Glu   1 5 10 15 Val Asp Asp Lys Val Leu His Ala Ala Phe Ile Pro Phe Gly Asp Ile              20 25 30 Thr Asp Ile Gln Ile Pro Leu Asp Tyr Glu Thr Glu Lys His Arg Gly          35 40 45 Phe Ala Phe Val Glu Phe Glu Leu Ala Glu Asp Ala Ala Ala Ala Ile      50 55 60 Asp Asn Met Asn Glu Ser Glu Leu Phe Gly Arg Thr Ile Arg Val Asn  65 70 75 80 Leu Ala Lys Pro Met Arg Ile Lys Glu Gly Ser Ser Arg Pro Val Trp                  85 90 95 Ser Asp Asp Asp Trp Leu Lys Lys Phe Ser Gly Lys Thr Leu Glu Glu             100 105 110 Asn Lys Glu Glu Glu Gly Pro Glu Pro Pro Lys Ala Glu Ala Gln Glu         115 120 125 Gly Glu Pro Thr Ala Lys Lys Ala Arg Ser Asn Pro Gln Val Tyr Met     130 135 140 Asp Ile Lys Ile Gly Asn Lys Pro Ala Gly Arg Ile Gln Met Leu Leu 145 150 155 160 Arg Ser Asp Val Val Pro Met Thr Ala Glu Asn Phe Arg Cys Leu Cys                 165 170 175 Thr His Glu Lys Gly Phe Gly Phe Lys Gly Ser Ser Phe His Arg Ile             180 185 190 Ile Pro Gln Phe Met Cys Gln Gly Gly Asp Phe Thr Asn His Asn Gly         195 200 205 Thr Gly Gly Lys Ser Ile Tyr Gly Lys Lys Phe Asp Asp Glu Asn Phe     210 215 220 Ile Leu Lys His Thr Gly Pro Gly Leu Leu Ser Met Ala Asn Ser Gly 225 230 235 240 Pro Asn Thr Asn Gly Ser Gln Phe Phe Leu Thr Cys Asp Lys Thr Asp                 245 250 255 Trp Leu Asp Gly Lys His Val Val Phe Gly Glu Val Thr Glu Gly Leu             260 265 270 Asp Val Leu Arg Gln Ile Glu Ala Gln Gly Ser Lys Asp Gly Lys Pro         275 280 285 Lys Gln Lys Val Met Ile Ala Asp Cys Gly Glu Tyr Met     290 295 300 <210> 4 <211> 281 <212> PRT <213> Mus musculus <400> 4 Met Ala Thr Asn Phe Leu Ala His Glu Lys Ile Trp Phe Asp Lys Phe   1 5 10 15 Lys Tyr Asp Asp Ala Glu Arg Arg Phe Tyr Glu Gln Met Asn Gly Pro              20 25 30 Val Thr Ser Gly Ser Arg Gln Glu Asn Gly Ala Ser Val Ile Leu Arg          35 40 45 Asp Ile Ala Arg Ala Arg Glu Asn Ile Gln Lys Ser Leu Ala Gly Ser      50 55 60 Ser Gly Pro Gly Ala Ser Ser Gly Pro Gly Gly Asp His Ser Glu Leu  65 70 75 80 Ile Val Arg Ile Thr Ser Leu Glu Val Glu Asn Gln Asn Leu Arg Gly                  85 90 95 Val Val Gln Asp Leu Gln Gln Ala Ile Ser Lys Leu Glu Ala Arg Leu             100 105 110 Ser Ser Leu Glu Lys Ser Ser Pro Thr Pro Arg Ala Thr Ala Pro Gln         115 120 125 Thr Gln His Val Ser Pro Met Arg Gln Val Glu Pro Pro Thr Lys Lys     130 135 140 Gly Ala Thr Pro Ala Glu Asp Asp Glu Asp Lys Asp Ile Asp Leu Phe 145 150 155 160 Gly Ser Asp Glu Glu Glu Glu Asp Lys Glu Ala Ala Arg Leu Arg Glu                 165 170 175 Glu Arg Leu Arg Gln Tyr Ala Glu Lys Lys Ala Lys Lys Pro Thr Leu             180 185 190 Val Ala Lys Ser Ser Ile Leu Leu Asp Val Lys Pro Trp Asp Asp Glu         195 200 205 Thr Asp Met Ala Gln Leu Glu Thr Cys Val Arg Ser Ile Gln Leu Asp     210 215 220 Gly Leu Val Trp Gly Ala Ser Lys Leu Val Pro Val Gly Tyr Gly Ile 225 230 235 240 Arg Lys Leu Gln Ile Gln Cys Val Val Glu Asp Asp Lys Val Gly Thr                 245 250 255 Asp Leu Leu Glu Glu Glu Ile Thr Lys Phe Glu Glu His Val Gln Ser             260 265 270 Val Asp Ile Ala Ala Phe Asn Lys Ile         275 280 <210> 5 <211> 203 <212> PRT <213> Mus musculus <400> 5 Met Ala Ala Ala Lys Asp Ser His Glu Asp His Asp Thr Ser Thr Glu   1 5 10 15 Asn Ala Asp Glu Ser Asn His Asp Pro Gln Phe Glu Pro Ile Val Ser              20 25 30 Leu Pro Glu Gln Glu Ile Lys Thr Leu Glu Glu Asp Glu Glu Glu Leu          35 40 45 Phe Lys Met Arg Ala Lys Leu Phe Arg Phe Ala Ser Glu Asn Asp Leu      50 55 60 Pro Glu Trp Lys Glu Arg Gly Thr Gly Asp Val Lys Leu Leu Lys His  65 70 75 80 Lys Glu Lys Gly Thr Ile Arg Leu Leu Met Arg Arg Asp Lys Thr Leu                  85 90 95 Lys Ile Cys Ala Asn His Tyr Ile Thr Pro Met Met Glu Leu Lys Pro             100 105 110 Asn Ala Gly Ser Asp Arg Ala Trp Val Trp Asn Thr His Ala Asp Phe         115 120 125 Ala Asp Glu Cys Pro Lys Pro Glu Leu Leu Ala Ile Arg Phe Leu Asn     130 135 140 Ala Glu Asn Ala Gln Lys Phe Lys Thr Lys Phe Glu Glu Cys Arg Lys 145 150 155 160 Glu Ile Glu Glu Arg Glu Lys Lys Gly Pro Gly Lys Asn Asp Asn Ala                 165 170 175 Glu Lys Val Ala Glu Lys Leu Glu Ala Leu Ser Val Arg Glu Ala Arg             180 185 190 Glu Glu Ala Glu Glu Lys Ser Glu Glu Lys Gln         195 200 <210> 6 <211> 529 <212> PRT <213> Mus musculus <400> 6 Met Leu Ser Leu Val Gly Arg Val Ala Ser Ala Ser Ala Ser Gly Ala   1 5 10 15 Leu Arg Gly Leu Ser Pro Ser Ala Ala Leu Pro Gln Ala Gln Leu Leu              20 25 30 Leu Arg Ala Ala Pro Ala Gly Val His Pro Ala Arg Asp Tyr Ala Ala          35 40 45 Gln Ala Ser Ala Ala Pro Lys Ala Gly Thr Ala Thr Gly Arg Ile Val      50 55 60 Ala Val Ile Gly Ala Val Val Asp Val Gln Phe Asp Glu Gly Leu Pro  65 70 75 80 Pro Ile Leu Asn Ala Leu Glu Val Gln Gly Arg Asp Ser Arg Leu Val                  85 90 95 Leu Glu Val Ala Gln His Leu Gly Glu Ser Thr Val Arg Thr Ile Ala             100 105 110 Met Asp Gly Thr Glu Gly Leu Val Arg Gly Gln Lys Val Leu Asp Ser         115 120 125 Gly Ala Pro Ile Lys Ile Pro Val Gly Pro Glu Thr Leu Gly Arg Ile     130 135 140 Met Asn Val Ile Gly Glu Pro Ile Asp Glu Arg Gly Pro Ile Lys Thr 145 150 155 160 Lys Gln Phe Ala Pro Ile His Ala Glu Ala Pro Glu Phe Ile Glu Met                 165 170 175 Ser Val Glu Gln Glu Ile Leu Val Thr Gly Ile Lys Val Val Asp Leu             180 185 190 Leu Ala Pro Tyr Ala Lys Gly Gly Lys Ile Gly Leu Phe Gly Gly Ala         195 200 205 Gly Val Gly Lys Thr Val Leu Ile Met Glu Leu Ile Asn Asn Val Ala     210 215 220 Lys Ala His Gly Gly Tyr Ser Val Phe Ala Gly Val Gly Glu Arg Thr 225 230 235 240 Arg Glu Gly Asn Asp Leu Tyr His Glu Met Ile Glu Ser Gly Val Ile                 245 250 255 Asn Leu Lys Asp Ala Thr Ser Lys Val Ala Leu Val Tyr Gly Gln Met             260 265 270 Asn Glu Pro Pro Gly Ala Arg Ala Arg Val Ala Leu Thr Gly Leu Thr         275 280 285 Val Ala Glu Tyr Phe Arg Asp Gln Glu Gly Gln Asp Val Leu Leu Phe     290 295 300 Ile Asp Asn Ile Phe Arg Phe Thr Gln Ala Gly Ser Glu Val Ser Ala 305 310 315 320 Leu Leu Gly Arg Ile Pro Ser Ala Val Gly Tyr Gln Pro Thr Leu Ala                 325 330 335 Thr Asp Met Gly Thr Met Gln Glu Arg Ile Thr Thr Thr Lys Lys Gly             340 345 350 Ser Ile Thr Ser Val Gln Ala Ile Tyr Val Pro Ala Asp Asp Leu Thr         355 360 365 Asp Pro Ala Pro Ala Thr Thr Phe Ala His Leu Asp Ala Thr Thr Val     370 375 380 Leu Ser Arg Ala Ile Ala Glu Leu Gly Ile Tyr Pro Ala Val Asp Pro 385 390 395 400 Leu Asp Ser Thr Ser Arg Ile Met Asp Pro Asn Ile Val Gly Asn Glu                 405 410 415 His Tyr Asp Val Ala Arg Gly Val Gln Lys Ile Leu Gln Asp Tyr Lys             420 425 430 Ser Leu Gln Asp Ile Ile Ala Ile Leu Gly Met Asp Glu Leu Ser Glu         435 440 445 Glu Asp Lys Leu Thr Val Ser Arg Ala Arg Lys Ile Gln Arg Phe Leu     450 455 460 Ser Gln Pro Phe Gln Val Ala Glu Val Phe Thr Gly His Met Gly Lys 465 470 475 480 Leu Val Pro Leu Lys Glu Thr Ile Lys Gly Phe Gln Gln Ile Leu Ala                 485 490 495 Gly Glu Tyr Asp His Leu Pro Glu Gln Ala Phe Tyr Met Val Gly Pro             500 505 510 Ile Glu Glu Ala Val Ala Lys Ala Asp Lys Leu Ala Glu Glu His Gly         515 520 525 Ser     <210> 7 <211> 130 <212> PRT <213> Mus musculus <400> 7 Met Ala Glu Tyr Gly Thr Leu Leu Gln Asp Leu Thr Asn Asn Ile Thr   1 5 10 15 Leu Glu Asp Leu Glu Gln Leu Lys Ser Ala Cys Lys Glu Asp Ile Pro              20 25 30 Ser Glu Lys Ser Glu Glu Ile Thr Thr Gly Ser Ala Trp Phe Ser Phe          35 40 45 Leu Glu Ser His Asn Lys Leu Asp Lys Asp Asn Leu Ser Tyr Ile Glu      50 55 60 His Ile Phe Glu Ile Ser Arg Arg Pro Asp Leu Leu Thr Met Val Val  65 70 75 80 Asp Tyr Arg Thr Arg Val Leu Lys Ile Ser Glu Glu Glu Glu Leu Asp                  85 90 95 Thr Lys Leu Thr Arg Ile Pro Ser Ala Lys Lys Tyr Lys Asp Ile Ile             100 105 110 Arg Gln Pro Ser Glu Glu Glu Ile Ile Lys Leu Ala Pro Pro Lys         115 120 125 Lys ala     130 <210> 8 <211> 574 <212> PRT <213> Mus musculus <400> 8 Met Glu Thr Pro Ser Gln Arg Arg Ala Thr Arg Ser Gly Ala Gln Ala   1 5 10 15 Ser Ser Thr Pro Leu Ser Pro Thr Arg Ile Thr Arg Leu Gln Glu Lys              20 25 30 Glu Asp Leu Gln Glu Leu Asn Asp Arg Leu Ala Val Tyr Ile Asp Arg          35 40 45 Val Arg Ser Leu Glu Thr Glu Asn Ala Gly Leu Arg Leu Arg Ile Thr      50 55 60 Glu Ser Glu Glu Val Val Ser Arg Glu Val Ser Gly Ile Lys Ala Ala  65 70 75 80 Tyr Glu Ala Glu Leu Gly Asp Ala Arg Lys Thr Leu Asp Ser Val Ala                  85 90 95 Lys Glu Arg Ala Arg Leu Gln Leu Glu Leu Ser Lys Val Arg Glu Glu             100 105 110 Phe Lys Glu Leu Lys Ala Arg Asn Thr Lys Lys Glu Gly Asp Leu Leu         115 120 125 Ala Ala Gln Ala Arg Leu Lys Asp Leu Glu Ala Leu Leu Asn Ser Lys     130 135 140 Glu Ala Ala Leu Ser Thr Ala Leu Ser Glu Lys Arg Thr Leu Glu Gly 145 150 155 160 Glu Leu His Asp Leu Arg Gly Gln Val Ala Lys Leu Glu Ala Ala Leu                 165 170 175 Gly Glu Ala Lys Lys Gln Leu Gln Asp Glu Met Leu Arg Arg Val Asp             180 185 190 Ala Glu Asn Arg Leu Gln Thr Leu Lys Glu Glu Leu Asp Phe Gln Lys         195 200 205 Asn Ile Tyr Ser Glu Glu Leu Arg Glu Thr Lys Arg Arg His Glu Thr     210 215 220 Arg Leu Val Glu Ile Asp Asn Gly Lys Gln Arg Glu Phe Glu Ser Arg 225 230 235 240 Leu Ala Asp Ala Leu Gln Glu Leu Arg Ala Gln His Glu Asp Gln Val                 245 250 255 Glu Gln Tyr Lys Lys Glu Leu Glu Lys Thr Tyr Ser Ala Lys Leu Asp             260 265 270 Asn Ala Arg Gln Ser Ala Glu Arg Asn Ser Asn Leu Val Gly Ala Ala         275 280 285 His Glu Glu Leu Gln Gln Ser Arg Ile Arg Ile Asp Ser Leu Ser Ala     290 295 300 Gln Leu Ser Gln Leu Gln Lys Gln Leu Ala Ala Lys Glu Ala Lys Leu 305 310 315 320 Arg Asp Leu Glu Asp Ser Leu Ala Arg Glu Arg Asp Thr Ser Arg Arg                 325 330 335 Leu Leu Ala Glu Lys Glu Arg Glu Met Ala Glu Met Arg Ala Arg Met             340 345 350 Gln Gln Gln Leu Asp Glu Tyr Gln Glu Leu Leu Asp Ile Lys Leu Ala         355 360 365 Leu Asp Met Glu Ile His Ala Tyr Arg Lys Leu Leu Glu Gly Glu Glu     370 375 380 Glu Arg Leu Arg Leu Ser Pro Ser Pro Thr Ser Gln Arg Ser Arg Gly 385 390 395 400 Arg Ala Ser Ser His Ser Ser Gln Ser Gln Gly Gly Gly Ser Val Thr                 405 410 415 Lys Lys Arg Lys Leu Glu Ser Ser Glu Ser Arg Ser Ser Phe Ser Gln             420 425 430 His Ala Arg Thr Ser Gly Arg Val Ala Val Glu Glu Val Asp Glu Glu         435 440 445 Gly Lys Phe Val Arg Leu Arg Asn Lys Ser Asn Glu Asp Gln Ser Met     450 455 460 Gly Asn Trp Gln Ile Arg Arg Gln Asn Gly Asp Asp Pro Leu Met Thr 465 470 475 480 Tyr Arg Phe Pro Pro Lys Phe Thr Leu Lys Ala Gly Gln Val Val Thr                 485 490 495 Ile Trp Ala Ser Gly Ala Gly Ala Thr His Ser Pro Pro Thr Asp Leu             500 505 510 Val Trp Lys Ala Gln Asn Thr Trp Gly Cys Gly Ser Ser Leu Arg Thr         515 520 525 Ala Leu Ile Asn Ser Thr Gly Glu Glu Val Ala Met Arg Lys Leu Val     530 535 540 Arg Ser Leu Thr Met Val Glu Asp Asn Glu Asp Asp Asp Glu Asp Gly 545 550 555 560 Glu Glu Leu Leu His His His Arg Val Ser Gly Ser Arg Arg                 565 570 <210> 9 <211> 706 <212> PRT <213> Mus musculus <400> 9 Met Ala Cys Glu Leu Arg Ala Val Leu Leu Trp Gly Arg Gly Leu Gln   1 5 10 15 Thr Val Leu Arg Ala Pro Ala Leu Ala Gly Val Arg Arg Gly Lys Pro              20 25 30 Val Leu His Leu Gln Lys Thr Thr Val Gln Phe Arg Gly Pro Thr Gln          35 40 45 Ser Leu Ala Ser Gly Ile Ser Ala Gly Gln Leu Tyr Ser Thr Gln Ala      50 55 60 Ala Glu Asp Lys Glu Glu Glu Ser Leu His Ser Ile Ile Ser Asn Thr  65 70 75 80 Glu Ala Val Arg Gly Ser Val Ser Lys His Glu Phe Gln Ala Glu Thr                  85 90 95 Lys Lys Leu Leu Asp Ile Val Ala Arg Ser Leu Tyr Ser Glu Lys Glu             100 105 110 Val Phe Ile Arg Glu Leu Ile Ser Asn Ala Ser Asp Ala Leu Glu Lys         115 120 125 Leu Arg His Lys Leu Val Cys Glu Gly Gln Val Leu Pro Glu Met Glu     130 135 140 Ile His Leu Gln Thr Asp Ala Lys Lys Gly Thr Ile Thr Ile Gln Asp 145 150 155 160 Thr Gly Ile Gly Met Thr Gln Glu Glu Leu Val Ser Asn Leu Gly Thr                 165 170 175 Ile Ala Arg Ser Gly Ser Lys Ala Phe Leu Glu Ala Leu Gln Asn Gln             180 185 190 Ala Glu Thr Ser Ser Lys Ile Ile Gly Gln Phe Gly Val Gly Phe Tyr         195 200 205 Ser Ala Phe Met Val Ala Asp Lys Val Glu Val Tyr Ser Arg Ser Ala     210 215 220 Ala Pro Glu Ser Pro Gly Tyr Gln Trp Leu Ser Asp Gly Ser Gly Val 225 230 235 240 Phe Glu Ile Ala Glu Ala Ser Gly Val Arg Pro Gly Thr Lys Ile Ile                 245 250 255 Ile His Leu Lys Ser Asp Cys Lys Asp Phe Ala Ser Glu Ser Arg Val             260 265 270 Gln Asp Val Val Thr Lys Tyr Ser Asn Phe Val Ser Phe Pro Leu Tyr         275 280 285 Leu Asn Gly Lys Arg Ile Asn Thr Leu Gln Ala Ile Trp Met Met Asp     290 295 300 Pro Lys Asp Ile Ser Glu Phe Gln His Glu Glu Phe Tyr Arg Tyr Ile 305 310 315 320 Ala Gln Ala Tyr Asp Lys Pro Arg Phe Thr Leu His Tyr Lys Thr Asp                 325 330 335 Ala Pro Leu Asn Ile Arg Ser Ile Phe Tyr Val Pro Glu Met Lys Pro             340 345 350 Ser Met Phe Asp Val Ser Arg Glu Leu Gly Ser Ser Val Ala Leu Tyr         355 360 365 Ser Arg Lys Val Leu Ile Gln Thr Lys Ala Ala Asp Ile Leu Pro Lys     370 375 380 Trp Leu Arg Phe Ile Arg Gly Val Val Asp Ser Glu Asp Ile Pro Leu 385 390 395 400 Asn Leu Ser Arg Glu Leu Leu Gln Glu Ser Ala Leu Ile Arg Lys Leu                 405 410 415 Arg Asp Val Leu Gln Gln Arg Leu Ile Lys Phe Phe Ile Asp Gln Ser             420 425 430 Lys Lys Asp Ala Glu Lys Tyr Ala Lys Phe Phe Glu Asp Tyr Gly Leu         435 440 445 Phe Met Arg Glu Gly Ile Val Thr Thr Ala Glu Gln Asp Ile Lys Glu     450 455 460 Asp Ile Ala Lys Leu Leu Arg Tyr Glu Ser Ser Ala Leu Pro Ala Gly 465 470 475 480 Gln Leu Thr Ser Leu Pro Asp Tyr Ala Ser Arg Met Gln Ala Gly Thr                 485 490 495 Arg Asn Ile Tyr Tyr Leu Cys Ala Pro Asn Arg His Leu Ala Glu His             500 505 510 Ser Pro Tyr Tyr Glu Ala Met Lys Gln Lys His Thr Glu Val Leu Phe         515 520 525 Cys Tyr Glu Gln Phe Asp Glu Leu Thr Leu Leu His Leu Arg Glu Phe     530 535 540 Asp Lys Lys Lys Leu Ile Ser Val Glu Thr Asp Ile Val Val Asp His 545 550 555 560 Tyr Lys Glu Glu Lys Phe Glu Asp Thr Ser Pro Ala Asp Glu Arg Leu                 565 570 575 Ser Glu Lys Glu Thr Glu Asp Leu Met Ala Trp Met Arg Asn Ala Leu             580 585 590 Gly Ser Arg Val Thr Asn Val Lys Val Thr Phe Arg Leu Asp Thr His         595 600 605 Pro Ala Met Val Thr Val Leu Glu Met Gly Ala Ala Arg His Phe Leu     610 615 620 Arg Met Gln Gln Leu Ala Lys Thr Gln Glu Glu Arg Ala Gln Leu Leu 625 630 635 640 Gln Pro Thr Leu Glu Ile Asn Pro Arg His Thr Leu Ile Lys Lys Leu                 645 650 655 Cys Gln Leu Arg Glu Ser Glu Pro Glu Leu Ala Gln Leu Leu Val Asp             660 665 670 Gln Ile Tyr Glu Asn Ala Met Ile Ala Ala Gly Leu Val Asp Asp Pro         675 680 685 Arg Ala Met Val Gly Arg Leu Asn Asp Leu Leu Val Lys Val Leu Glu     690 695 700 Lys his 705 <210> 10 <211> 509 <212> PRT <213> Mus musculus <400> 10 Met Ala Ala Ile Gly Val His Leu Gly Cys Thr Ser Ala Cys Val Ala   1 5 10 15 Val Tyr Lys Asp Gly Arg Ala Asp Val Val Ala Asn Asp Ala Gly Asp              20 25 30 Arg Val Thr Pro Ala Ile Val Ala Tyr Ser Glu Arg Glu Gln Val Val          35 40 45 Gly Leu Ala Ala Lys Gln Ser Arg Ile Arg His Val Ser Ser Thr Val      50 55 60 Val Lys Val Lys Gln Ile Leu Gly Arg Ser Ser Ala Asp Pro Gln Ala  65 70 75 80 Gln Lys Tyr Ile Ser Glu Ser Lys Cys Leu Val Ile Glu Lys Asn Gly                  85 90 95 Lys Leu Arg Tyr Glu Ile Asp Thr Gly Glu Glu Thr Lys Leu Val Asn             100 105 110 Pro Glu Asp Val Ala Arg Leu Ile Phe Ser Lys Met Lys Glu Thr Ala         115 120 125 His Ser Val Leu Gly Ser Asp Ala Asn Asp Val Val Val Thr Val Pro     130 135 140 Phe Asp Phe Gly Glu Lys Gln Lys Ser Ala Leu Gly Glu Ala Ala Gly 145 150 155 160 Ala Ala Gly Phe Asn Val Leu Arg Leu Ile His Glu Pro Ser Ala Ala                 165 170 175 Leu Leu Ala Tyr Gly Ile Gly Gln Asp His Pro Thr Gly Lys Ser Asn             180 185 190 Val Leu Val Phe Lys Leu Gly Gly Thr Ser Leu Ser Leu Ser Val Met         195 200 205 Glu Val Asn Ser Gly Met Tyr Arg Val Leu Ser Thr Asn Thr Ser Asp     210 215 220 Asn Ile Gly Gly Ala His Phe Thr Asp Thr Leu Ala Gln Tyr Leu Ala 225 230 235 240 Ser Glu Phe Gln Arg Leu Phe Lys His Asp Val Arg Gly Asn Ala Arg                 245 250 255 Ala Met Met Lys Leu Met Asn Ser Ala Glu Val Ala Lys His Ser Leu             260 265 270 Ser Thr Leu Gly Ser Ala Asn Cys Phe Val Asp Ser Leu Tyr Glu Gly         275 280 285 Gln Asp Phe Asp Cys Asn Val Ser Arg Ala Arg Phe Glu Leu Leu Cys     290 295 300 Ser Pro Leu Phe Asn Lys Cys Thr Glu Ala Ile Arg Glu Leu Leu Arg 305 310 315 320 Gln Thr Gly Phe Thr Ala Asp Asp Ile Asn Lys Val Val Leu Cys Gly                 325 330 335 Gly Ser Ser Arg Ile Pro Lys Leu Gln Gln Leu Ile Lys Asp Leu Phe             340 345 350 Pro Ala Val Asp Leu Leu Asn Ser Ile Pro Pro Asp Glu Val Ile Pro         355 360 365 Ile Gly Ala Ala Ile Glu Ala Gly Ile Leu Val Gly Lys Glu Ser Thr     370 375 380 Ser Gly Asp Asp Ser Val Met Ile Glu Cys Ser Ala Lys Asp Ile Leu 385 390 395 400 Val Lys Gly Val Asp Glu Ser Gly Ala Asp Arg Phe Thr Val Leu Phe                 405 410 415 Pro Ser Gly Thr Pro Leu Pro Ala Arg Arg Gln His Thr Leu Gln Ala             420 425 430 Pro Gly Arg Val Ser Ser Val Cys Leu Glu Leu Tyr Glu Ser Glu Gly         435 440 445 Lys Asn Ser Ala Lys Glu Glu Ala Lys Phe Ala Gln Val Val Leu Gln     450 455 460 Asp Leu Asp Lys Lys Glu Asn Gly Leu Arg Asp Ile Leu Ala Val Leu 465 470 475 480 Thr Met Lys Arg Asp Gly Ser Leu Gln Val Thr Cys Thr Asp Gln Asp                 485 490 495 Thr Gly Lys Cys Glu Ala Ile Thr Val Glu Val Ala Ser             500 505 <210> 11 <211> 458 <212> PRT <213> Mus musculus <400> 11 Met Thr Ala Glu Glu Met Lys Ala Ala Glu Asn Gly Ala Gln Ser Ala   1 5 10 15 Pro Leu Pro Leu Glu Gly Val Asp Ile Ser Pro Lys Gln Asp Glu Gly              20 25 30 Val Leu Lys Val Ile Lys Arg Glu Gly Thr Gly Thr Glu Thr Pro Met          35 40 45 Ile Gly Asp Arg Val Phe Val His Tyr Thr Gly Trp Leu Leu Asp Gly      50 55 60 Thr Lys Phe Asp Ser Ser Leu Asp Arg Lys Asp Lys Phe Ser Phe Asp  65 70 75 80 Leu Gly Lys Gly Glu Val Ile Lys Ala Trp Asp Ile Ala Val Ala Thr                  85 90 95 Met Lys Val Gly Glu Val Cys His Ile Thr Cys Lys Pro Glu Tyr Ala             100 105 110 Tyr Gly Ala Ala Gly Ser Pro Pro Lys Ile Pro Pro Asn Ala Thr Leu         115 120 125 Val Phe Glu Val Glu Leu Phe Glu Phe Lys Gly Glu Asp Leu Thr Glu     130 135 140 Glu Glu Asp Gly Gly Ile Ile Arg Arg Ile Arg Thr Arg Gly Glu Gly 145 150 155 160 Tyr Ala Arg Pro Asn Asp Gly Ala Met Val Glu Val Ala Leu Glu Gly                 165 170 175 Tyr His Lys Asp Arg Leu Phe Asp Gln Arg Glu Leu Cys Phe Glu Val             180 185 190 Gly Glu Gly Glu Ser Leu Asp Leu Pro Cys Gly Leu Glu Glu Ala Ile         195 200 205 Gln Arg Met Glu Lys Gly Glu His Ser Ile Val Tyr Leu Lys Pro Ser     210 215 220 Tyr Ala Phe Gly Ser Val Gly Lys Glu Arg Phe Gln Ile Pro Pro His 225 230 235 240 Ala Glu Leu Arg Tyr Glu Val Arg Leu Lys Ser Phe Glu Lys Ala Lys                 245 250 255 Glu Ser Trp Glu Met Ser Ser Ala Glu Lys Leu Glu Gln Ser Asn Ile             260 265 270 Val Lys Glu Arg Gly Thr Ala Tyr Phe Lys Glu Gly Lys Tyr Lys Gln         275 280 285 Ala Leu Leu Gln Tyr Lys Lys Ile Val Ser Trp Leu Glu Tyr Glu Ser     290 295 300 Ser Phe Ser Gly Glu Glu Met Gln Lys Val His Ala Leu Arg Leu Ala 305 310 315 320 Ser His Leu Asn Leu Ala Met Cys His Leu Lys Leu Gln Ala Phe Ser                 325 330 335 Ala Ala Ile Glu Ser Cys Asn Lys Ala Leu Glu Leu Asp Ser Asn Asn             340 345 350 Glu Lys Gly Leu Phe Arg Arg Gly Glu Ala His Leu Ala Val Asn Asp         355 360 365 Phe Asp Leu Ala Arg Ala Asp Phe Gln Lys Val Leu Gln Leu Tyr Pro     370 375 380 Ser Asn Lys Ala Ala Lys Thr Gln Leu Ala Val Cys Gln Gln Arg Thr 385 390 395 400 Arg Arg Gln Leu Ala Arg Glu Lys Lys Leu Tyr Ala Asn Met Phe Glu                 405 410 415 Arg Leu Ala Glu Glu Glu His Lys Val Lys Ala Glu Val Ala Ala Gly             420 425 430 Asp His Pro Thr Asp Ala Glu Met Lys Gly Glu Arg Asn Asn Val Ala         435 440 445 Glu Asn Gln Ser Arg Val Glu Thr Glu Ala     450 455 <210> 12 <211> 370 <212> PRT <213> Mus musculus <400> 12 Met Ala Val Ala Ala Ala Ala Ala Ala Thr Ala Met Ser Ala Ala Gly   1 5 10 15 Gly Gly Gly Ala Ser Ala Ala Arg Ser Ile Ser Arg Phe Arg Gly Cys              20 25 30 Leu Ala Gly Ala Leu Leu Gly Asp Cys Val Gly Ala Val Tyr Glu Ala          35 40 45 His Asp Thr Val Ser Leu Ala Ser Val Leu Ser His Val Glu Ser Leu      50 55 60 Glu Pro Asp Pro Gly Thr Pro Gly Ser Ala Arg Thr Glu Thr Leu Tyr  65 70 75 80 Tyr Thr Asp Asp Thr Ala Met Thr Arg Ala Leu Val Gln Ser Leu Leu                  85 90 95 Ala Lys Glu Ala Phe Asp Glu Val Asp Met Ala His Arg Phe Ala Gln             100 105 110 Glu Tyr Lys Lys Asp Pro Asp Arg Gly Tyr Gly Ala Gly Val Ile Thr         115 120 125 Val Phe Lys Lys Leu Leu Asn Pro Lys Cys Arg Asp Val Tyr Glu Pro     130 135 140 Ala Arg Ala Gln Phe Asn Gly Lys Gly Ser Tyr Gly Asn Gly Gly Ala 145 150 155 160 Met Arg Val Ala Gly Ile Ser Leu Ala Tyr Ser Ser Val Gln Asp Val                 165 170 175 Gln Lys Phe Ala Arg Leu Ser Ala Gln Leu Thr His Ala Ser Ser Leu             180 185 190 Gly Tyr Asn Gly Ala Ile Leu Gln Ala Leu Ala Val His Leu Ala Leu         195 200 205 Gln Gly Val Ser Ser Ser Glu His Phe Leu Glu Gln Leu Leu Gly His     210 215 220 Met Glu Glu Leu Glu Gly Asp Ala Gln Ser Val Leu Asp Ala Lys Glu 225 230 235 240 Leu Gly Met Glu Glu Arg Pro Tyr Ser Ser Arg Leu Lys Lys Val Gly                 245 250 255 Glu Leu Leu Asp Gln Asp Val Val Ser Arg Glu Glu Val Val Ser Glu             260 265 270 Leu Gly Asn Gly Ile Ala Ala Phe Glu Ser Val Pro Thr Ala Ile Tyr         275 280 285 Cys Phe Leu Arg Cys Met Glu Pro His Pro Glu Ile Pro Ser Thr Phe     290 295 300 Asn Ser Leu Gln Arg Thr Leu Ile Tyr Ser Ile Ser Leu Gly Gly Asp 305 310 315 320 Thr Asp Thr Ile Ala Thr Met Ala Gly Ala Ile Ala Gly Ala Tyr Tyr                 325 330 335 Gly Met Glu Gln Val Pro Glu Ser Trp Gln Gln Ser Cys Glu Gly Phe             340 345 350 Glu Glu Thr Asp Val Leu Ala Gln Ser Leu His Arg Val Phe Gln Glu         355 360 365 Ser Ser     370 <210> 13 <211> 271 <212> PRT <213> Mus musculus <400> 13 Met Ala Ala Glu Glu Pro Gln Gln Gln Lys Gln Glu Pro Leu Gly Ser   1 5 10 15 Asp Ser Glu Gly Val Asn Cys Leu Ala Tyr Asp Glu Ala Ile Met Ala              20 25 30 Gln Gln Asp Arg Ile Gln Gln Glu Ile Ala Val Gln Asn Pro Leu Val          35 40 45 Ser Glu Arg Leu Glu Leu Ser Val Leu Tyr Lys Glu Tyr Ala Glu Asp      50 55 60 Asp Asn Ile Tyr Gln Gln Lys Ile Lys Asp Leu His Lys Lys Tyr Ser  65 70 75 80 Tyr Ile Arg Lys Thr Arg Pro Asp Gly Asn Cys Phe Tyr Arg Ala Phe                  85 90 95 Gly Phe Ser His Leu Glu Ala Leu Leu Asp Asp Ser Lys Glu Leu Gln             100 105 110 Arg Phe Lys Ala Val Ser Ala Lys Ser Lys Glu Asp Leu Val Ser Gln         115 120 125 Gly Phe Thr Glu Phe Thr Ile Glu Asp Phe His Asn Thr Phe Met Asp     130 135 140 Leu Ile Glu Gln Val Glu Lys Gln Thr Ser Val Ala Asp Leu Leu Ala 145 150 155 160 Ser Phe Asn Asp Gln Ser Thr Ser Asp Tyr Leu Val Val Tyr Leu Arg                 165 170 175 Leu Leu Thr Ser Gly Tyr Leu Gln Arg Glu Ser Lys Phe Phe Glu His             180 185 190 Phe Ile Glu Gly Gly Arg Thr Val Lys Glu Phe Cys Gln Gln Glu Val         195 200 205 Glu Pro Met Cys Lys Glu Ser Asp His Ile His Ile Ile Ala Leu Ala     210 215 220 Gln Ala Leu Ser Val Ser Ile Gln Val Glu Tyr Met Asp Arg Gly Glu 225 230 235 240 Gly Gly Thr Thr Asn Pro His Val Phe Pro Glu Gly Ser Glu Pro Lys                 245 250 255 Val Tyr Leu Leu Tyr Arg Pro Gly His Tyr Asp Ile Leu Tyr Lys             260 265 270 <210> 14 <211> 244 <212> PRT <213> Mus musculus <400> 14 Met Asp Lys Ser Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala   1 5 10 15 Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Ala Val Thr Glu Gln              20 25 30 Gly His Glu Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr          35 40 45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser Ser      50 55 60 Ile Glu Gln Lys Thr Glu Arg Asn Glu Lys Lys Gln Gln Met Gly Lys  65 70 75 80 Glu Tyr Arg Glu Lys Ile Glu Ala Glu Leu Gln Asp Ile Cys Asn Asp                  85 90 95 Val Leu Glu Leu Leu Asp Lys Tyr Leu Ile Leu Asn Ala Thr Gln Ala             100 105 110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Phe Arg Tyr         115 120 125 Leu Ser Glu Val Ala Ser Gly Glu Asn Lys Gln Thr Thr Val Ser Asn     130 135 140 Ser Gln Gln Ala Tyr Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150 155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val                 165 170 175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala             180 185 190 Lys Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu         195 200 205 Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn     210 215 220 Leu Thr Leu Trp Thr Ser Glu Asn Gln Gly Asp Glu Gly Asp Ala Gly 225 230 235 240 Glu Gly Glu Asn                 <210> 15 <211> 15 <212> PRT <213> Mus musculus <400> 15 Leu Val Gly Gly Lys Asp Phe Glu Gln Pro Leu Ala Ile Ser Arg   1 5 10 15 <210> 16 <211> 12 <212> PRT <213> Mus musculus <400> 16 Ile Trp Ser Pro Leu Val Thr Glu Glu Gly Lys Arg   1 5 10 <210> 17 <211> 19 <212> PRT <213> Mus musculus <400> 17 Met Asn Leu Ala Ser Glu Pro Gln Glu Val Leu His Ile Gly Ser Ala   1 5 10 15 His Asn Arg             <210> 18 <211> 14 <212> PRT <213> Mus musculus <400> 18 Ser Ala Met Pro Phe Thr Ala Ser Pro Ala Pro Ser Thr Arg   1 5 10 <210> 19 <211> 28 <212> PRT <213> Mus musculus <400> 19 Val Ile Thr Asn Gln Tyr Asn Ser Pro Thr Gly Leu Tyr Ser Ser Glu   1 5 10 15 Asn Ile Ser Asn Phe Asn Asn Ala Val Glu Ser Lys              20 25 <210> 20 <211> 32 <212> PRT <213> Mus musculus <400> 20 Thr Ser Ala Ser Gly Glu Glu Ala Asn Ser Arg Pro Val Val Gln Pro   1 5 10 15 His Pro Ser Gly Ser Leu Ile Ile Asp Lys Asp Ser Glu Val Tyr Lys              20 25 30 <210> 21 <211> 27 <212> PRT <213> Mus musculus <400> 21 Gln Ser Thr Ser Phe Leu Val Leu Gln Glu Ile Leu Glu Ser Asp Gly   1 5 10 15 Lys Gly Asp Pro Asn Lys Pro Ser Gly Phe Arg              20 25 <210> 22 <211> 14 <212> PRT <213> Mus musculus <400> 22 Glu Asn Ser Val Leu Gly Ser Ile Gln Glu Glu Leu Gln Lys   1 5 10 <210> 23 <211> 13 <212> PRT <213> Mus musculus <400> 23 Thr Gly Gly Leu Asp Ser Leu Val Leu Ser Pro Gly Arg   1 5 10 <210> 24 <211> 10 <212> PRT <213> Mus musculus <400> 24 Trp Pro Val Ser Asp Asn Thr Ile Met His   1 5 10 <210> 25 <211> 16 <212> PRT <213> Mus musculus <400> 25 Tyr Val Glu Thr Val Glu Thr Leu Ser Glu His Arg Pro Asp Pro Ser   1 5 10 15 <210> 26 <211> 7 <212> PRT <213> Mus musculus <400> 26 Pro Leu Val Gln Trp Gly Arg   1 5 <210> 27 <211> 15 <212> PRT <213> Mus musculus <400> 27 His Met Ala Glu Tyr Gln Glu His Trp Phe Tyr Phe Glu Ala Lys   1 5 10 15 <210> 28 <211> 8 <212> PRT <213> Mus musculus <400> 28 Trp Gln Phe Tyr Leu Glu Glu Arg   1 5 <210> 29 <211> 20 <212> PRT <213> Mus musculus <400> 29 Ile Arg Glu Asp Ala Glu Asp Lys Val Thr Phe Pro Asp Asn Tyr Asp   1 5 10 15 Ala Glu Glu Arg              20 <210> 30 <211> 9 <212> PRT <213> Mus musculus <400> 30 Gly Leu Tyr Gln Glu Leu Glu His Lys   1 5 <210> 31 <211> 12 <212> PRT <213> Mus musculus <400> 31 Gly Arg Leu Glu Asp Leu Gly Ala Ala Leu His Arg   1 5 10 <210> 32 <211> 15 <212> PRT <213> Mus musculus <400> 32 Arg Val Leu Tyr Val Gly Gly Leu Ala Glu Glu Val Asp Asp Lys   1 5 10 15 <210> 33 <211> 25 <212> PRT <213> Mus musculus <400> 33 Val Leu His Ala Ala Phe Ile Pro Phe Gly Asp Ile Thr Asp Ile Gln   1 5 10 15 Ile Pro Leu Asp Tyr Glu Thr Glu Lys              20 25 <210> 34 <211> 11 <212> PRT <213> Mus musculus <400> 34 Pro Val Trp Ser Asp Asp Asp Trp Leu Lys Lys   1 5 10 <210> 35 <211> 26 <212> PRT <213> Mus musculus <400> 35 Thr Leu Glu Glu Asn Lys Glu Glu Glu Gly Pro Glu Pro Pro Lys Ala   1 5 10 15 Glu Ala Gln Glu Gly Glu Pro Thr Ala Lys              20 25 <210> 36 <211> 10 <212> PRT <213> Mus musculus <400> 36 Ser Asn Pro Gln Val Tyr Met Asp Ile Lys   1 5 10 <210> 37 <211> 12 <212> PRT <213> Mus musculus <400> 37 Ser Asp Val Val Pro Met Thr Ala Glu Asn Phe Arg   1 5 10 <210> 38 <211> 10 <212> PRT <213> Mus musculus <400> 38 Lys Phe Asp Asp Glu Asn Phe Ile Leu Lys   1 5 10 <210> 39 <211> 15 <212> PRT <213> Mus musculus <400> 39 His Val Val Phe Gly Glu Val Thr Glu Gly Leu Asp Val Leu Arg   1 5 10 15 <210> 40 <211> 15 <212> PRT <213> Mus musculus <400> 40 Arg Val Leu Tyr Val Gly Gly Leu Ala Glu Glu Val Asp Asp Lys   1 5 10 15 <210> 41 <211> 25 <212> PRT <213> Mus musculus <400> 41 Val Leu His Ala Ala Phe Ile Pro Phe Gly Asp Ile Thr Asp Ile Gln   1 5 10 15 Ile Pro Leu Asp Tyr Glu Thr Glu Lys              20 25 <210> 42 <211> 10 <212> PRT <213> Mus musculus <400> 42 Pro Val Trp Ser Asp Asp Asp Trp Leu Lys   1 5 10 <210> 43 <211> 26 <212> PRT <213> Mus musculus <400> 43 Thr Leu Glu Glu Asn Lys Glu Glu Glu Gly Pro Glu Pro Pro Lys Ala   1 5 10 15 Glu Ala Gln Glu Gly Glu Pro Thr Ala Lys              20 25 <210> 44 <211> 10 <212> PRT <213> Mus musculus <400> 44 Ser Asn Pro Gln Val Tyr Met Asp Ile Lys   1 5 10 <210> 45 <211> 12 <212> PRT <213> Mus musculus <400> 45 Ser Asp Val Val Pro Met Thr Ala Glu Asn Phe Arg   1 5 10 <210> 46 <211> 10 <212> PRT <213> Mus musculus <400> 46 Lys Phe Asp Asp Glu Asn Phe Ile Leu Lys   1 5 10 <210> 47 <211> 15 <212> PRT <213> Mus musculus <400> 47 His Val Val Phe Gly Glu Val Thr Glu Gly Leu Asp Val Leu Arg   1 5 10 15 <210> 48 <211> 34 <212> PRT <213> Mus musculus <400> 48 Asp Ser His Glu Asp His Asp Thr Ser Thr Glu Asn Ala Asp Glu Ser   1 5 10 15 Asn His Asp Pro Gln Phe Glu Pro Ile Val Ser Leu Pro Glu Gln Glu              20 25 30 Ile Lys         <210> 49 <211> 11 <212> PRT <213> Mus musculus <400> 49 Thr Leu Glu Glu Asp Glu Glu Glu Leu Phe Lys   1 5 10 <210> 50 <211> 11 <212> PRT <213> Mus musculus <400> 50 Phe Ala Ser Glu Asn Asp Leu Pro Glu Trp Lys   1 5 10 <210> 51 <211> 12 <212> PRT <213> Mus musculus <400> 51 Glu Leu Ile Ser Asn Ala Ser Asp Ala Leu Asp Lys   1 5 10 <210> 52 <211> 10 <212> PRT <213> Mus musculus <400> 52 Ile Asp Ile Ile Pro Asn Pro Gln Glu Arg   1 5 10 <210> 53 <211> 19 <212> PRT <213> Mus musculus <400> 53 Ser Glu Glu Ile Thr Thr Gly Ser Ala Trp Phe Ser Phe Leu Glu Ser   1 5 10 15 His Asn Lys             <210> 54 <211> 17 <212> PRT <213> Mus musculus <400> 54 Leu Asp Lys Asp Asn Leu Ser Tyr Ile Glu His Ile Phe Glu Ile Ser   1 5 10 15 Arg     <210> 55 <211> 12 <212> PRT <213> Mus musculus <400> 55 Arg Pro Asp Leu Leu Thr Met Val Val Asp Tyr Arg   1 5 10 <210> 56 <211> 13 <212> PRT <213> Mus musculus <400> 56 Leu Gln Glu Lys Glu Asp Leu Gln Glu Leu Asn Asp Arg   1 5 10 <210> 57 <211> 11 <212> PRT <213> Mus musculus <400> 57 Ala Ala Tyr Glu Ala Glu Leu Gly Asp Ala Arg   1 5 10 <210> 58 <211> 11 <212> PRT <213> Mus musculus <400> 58 Glu Ala Ala Leu Ser Thr Ala Leu Ser Glu Lys   1 5 10 <210> 59 <211> 16 <212> PRT <213> Mus musculus <400> 59 Asn Ser Asn Leu Val Gly Ala Ala His Glu Glu Leu Gln Gln Ser Arg   1 5 10 15 <210> 60 <211> 13 <212> PRT <213> Mus musculus <400> 60 Ile Asp Ser Leu Ser Ala Gln Leu Ser Gln Leu Gln Lys   1 5 10 <210> 61 <211> 14 <212> PRT <213> Mus musculus <400> 61 Thr Ala Leu Ile Asn Ser Thr Gly Glu Glu Val Ala Met Arg   1 5 10 <210> 62 <211> 24 <212> PRT <213> Mus musculus <400> 62 Ser Thr Gln Ala Ala Glu Asp Lys Glu Glu Glu Ser Leu His Ser Ile   1 5 10 15 Ile Ser Asn Thr Glu Ala Val Arg              20 <210> 63 <211> 8 <212> PRT <213> Mus musculus <400> 63 Lys Leu Leu Asp Ile Val Ala Arg   1 5 <210> 64 <211> 12 <212> PRT <213> Mus musculus <400> 64 Glu Leu Ile Ser Asn Ala Ser Asp Ala Leu Glu Lys   1 5 10 <210> 65 <211> 27 <212> PRT <213> Mus musculus <400> 65 Lys Gly Thr Ile Thr Ile Gln Asp Thr Gly Ile Gly Met Thr Gln Glu   1 5 10 15 Glu Leu Val Ser Asn Leu Gly Thr Ile Ala Arg              20 25 <210> 66 <211> 15 <212> PRT <213> Mus musculus <400> 66 Ala Phe Leu Glu Ala Leu Gln Asn Gln Ala Glu Thr Ser Ser Lys   1 5 10 15 <210> 67 <211> 32 <212> PRT <213> Mus musculus <400> 67 Ser Ala Ala Pro Glu Ser Pro Gly Tyr Gln Trp Leu Ser Asp Gly Ser   1 5 10 15 Gly Val Phe Glu Ile Ala Glu Ala Ser Gly Val Arg Pro Gly Thr Lys              20 25 30 <210> 68 <211> 14 <212> PRT <213> Mus musculus <400> 68 Tyr Ser Asn Phe Val Ser Phe Pro Leu Tyr Leu Asn Gly Lys   1 5 10 <210> 69 <211> 13 <212> PRT <213> Mus musculus <400> 69 Ile Asn Thr Leu Gln Ala Ile Trp Met Met Asp Pro Lys   1 5 10 <210> 70 <211> 12 <212> PRT <213> Mus musculus <400> 70 Asp Ile Ser Glu Phe Gln His Glu Glu Phe Tyr Arg   1 5 10 <210> 71 <211> 17 <212> PRT <213> Mus musculus <400> 71 Ser Ile Phe Tyr Val Pro Glu Met Lys Pro Ser Met Phe Asp Val Ser   1 5 10 15 Arg     <210> 72 <211> 11 <212> PRT <213> Mus musculus <400> 72 Glu Leu Gly Ser Ser Val Ala Leu Tyr Ser Arg   1 5 10 <210> 73 <211> 14 <212> PRT <213> Mus musculus <400> 73 Gly Val Val Asp Ser Glu Asp Ile Pro Leu Asn Leu Ser Arg   1 5 10 <210> 74 <211> 10 <212> PRT <213> Mus musculus <400> 74 Glu Leu Leu Gln Glu Ser Ala Leu Ile Arg   1 5 10 <210> 75 <211> 7 <212> PRT <213> Mus musculus <400> 75 Phe Phe Ile Asp Gln Ser Lys   1 5 <210> 76 <211> 10 <212> PRT <213> Mus musculus <400> 76 Phe Phe Glu Asp Tyr Gly Leu Phe Met Arg   1 5 10 <210> 77 <211> 17 <212> PRT <213> Mus musculus <400> 77 Glu Gly Ile Val Thr Thr Ala Glu Gln Asp Ile Lys Glu Asp Ile Ala   1 5 10 15 Lys     <210> 78 <211> 20 <212> PRT <213> Mus musculus <400> 78 Tyr Glu Ser Ser Ala Leu Pro Ala Gly Gln Leu Thr Ser Leu Pro Asp   1 5 10 15 Tyr Ala Ser Arg              20 <210> 79 <211> 13 <212> PRT <213> Mus musculus <400> 79 His Leu Ala Glu His Ser Pro Tyr Tyr Glu Ala Met Lys   1 5 10 <210> 80 <211> 17 <212> PRT <213> Mus musculus <400> 80 Leu Ile Ser Val Glu Thr Asp Ile Val Val Asp His Tyr Lys Glu Glu   1 5 10 15 Lys     <210> 81 <211> 14 <212> PRT <213> Mus musculus <400> 81 Leu Ser Glu Lys Glu Thr Glu Asp Leu Met Ala Trp Met Arg   1 5 10 <210> 82 <211> 9 <212> PRT <213> Mus musculus <400> 82 Val Thr Asn Val Lys Val Thr Phe Arg   1 5 <210> 83 <211> 17 <212> PRT <213> Mus musculus <400> 83 Leu Asp Thr His Pro Ala Met Val Thr Val Leu Glu Met Gly Ala Ala   1 5 10 15 Arg     <210> 84 <211> 13 <212> PRT <213> Mus musculus <400> 84 Ala Gln Leu Leu Gln Pro Thr Leu Glu Ile Asn Pro Arg   1 5 10 <210> 85 <211> 10 <212> PRT <213> Mus musculus <400> 85 Ile Ala Ala Gly Leu Val Asp Asp Pro Arg   1 5 10 <210> 86 <211> 11 <212> PRT <213> Mus musculus <400> 86 Val Thr Pro Ala Ile Val Ala Tyr Ser Glu Arg   1 5 10 <210> 87 <211> 12 <212> PRT <213> Mus musculus <400> 87 Leu Arg Tyr Glu Ile Asp Thr Gly Glu Glu Thr Lys   1 5 10 <210> 88 <211> 9 <212> PRT <213> Mus musculus <400> 88 Leu Val Asn Pro Glu Asp Val Ala Arg   1 5 <210> 89 <211> 16 <212> PRT <213> Mus musculus <400> 89 Ser Ala Leu Gly Glu Ala Ala Gly Ala Ala Gly Phe Asn Val Leu Arg   1 5 10 15 <210> 90 <211> 22 <212> PRT <213> Mus musculus <400> 90 Leu Ile His Glu Pro Ser Ala Ala Leu Leu Ala Tyr Gly Ile Gly Gln   1 5 10 15 Asp His Pro Thr Gly Lys              20 <210> 91 <211> 7 <212> PRT <213> Mus musculus <400> 91 Ser Asn Val Leu Val Phe Lys   1 5 <210> 92 <211> 19 <212> PRT <213> Mus musculus <400> 92 Leu Gly Gly Thr Ser Leu Ser Leu Ser Val Met Glu Val Asn Ser Gly   1 5 10 15 Met tyr arg             <210> 93 <211> 29 <212> PRT <213> Mus musculus <400> 93 Val Leu Ser Thr Asn Thr Ser Asp Asn Ile Gly Gly Ala His Phe Thr   1 5 10 15 Asp Thr Leu Ala Gln Tyr Leu Ala Ser Glu Phe Gln Arg              20 25 <210> 94 <211> 11 <212> PRT <213> Mus musculus <400> 94 Gln Thr Gly Phe Thr Ala Asp Asp Ile Asn Lys   1 5 10 <210> 95 <211> 23 <212> PRT <213> Mus musculus <400> 95 Gly Val Asp Glu Ser Gly Ala Asp Arg Phe Thr Val Leu Phe Pro Ser   1 5 10 15 Gly Thr Pro Leu Pro Ala Arg              20 <210> 96 <211> 12 <212> PRT <213> Mus musculus <400> 96 Phe Ala Gln Val Val Leu Gln Asp Leu Asp Lys Lys   1 5 10 <210> 97 <211> 9 <212> PRT <213> Mus musculus <400> 97 Asp Ile Leu Ala Val Leu Thr Met Lys   1 5 <210> 98 <211> 21 <212> PRT <213> Mus musculus <400> 98 Ala Ala Glu Asn Gly Ala Gln Ser Ala Pro Leu Pro Leu Glu Gly Val   1 5 10 15 Asp Ile Ser Pro Lys              20 <210> 99 <211> 14 <212> PRT <213> Mus musculus <400> 99 Gly Glu Asp Leu Thr Glu Glu Glu Asp Gly Gly Ile Ile Arg   1 5 10 <210> 100 <211> 15 <212> PRT <213> Mus musculus <400> 100 Arg Gly Glu Ala His Leu Ala Val Asn Asp Phe Asp Leu Ala Arg   1 5 10 15 <210> 101 <211> 19 <212> PRT <213> Mus musculus <400> 101 Val Leu Ser His Val Glu Ser Leu Glu Pro Asp Pro Gly Thr Pro Gly   1 5 10 15 Ser Ala Arg             <210> 102 <211> 14 <212> PRT <213> Mus musculus <400> 102 Thr Glu Thr Leu Tyr Tyr Thr Asp Asp Thr Ala Met Thr Arg   1 5 10 <210> 103 <211> 20 <212> PRT <213> Mus musculus <400> 103 Ala Leu Val Gln Ser Leu Leu Ala Lys Glu Ala Phe Asp Glu Val Asp   1 5 10 15 Met Ala His Arg              20 <210> 104 <211> 11 <212> PRT <213> Mus musculus <400> 104 Gly Tyr Gly Ala Gly Val Ile Thr Val Phe Lys   1 5 10 <210> 105 <211> 16 <212> PRT <213> Mus musculus <400> 105 Val Ala Gly Ile Ser Leu Ala Tyr Ser Ser Val Gln Asp Val Gln Lys   1 5 10 15 <210> 106 <211> 12 <212> PRT <213> Mus musculus <400> 106 Glu Leu Gly Met Glu Glu Arg Pro Tyr Ser Ser Arg   1 5 10 <210> 107 <211> 15 <212> PRT <213> Mus musculus <400> 107 Leu Lys Lys Val Gly Glu Leu Leu Asp Gln Asp Val Val Ser Arg   1 5 10 15 <210> 108 <211> 25 <212> PRT <213> Mus musculus <400> 108 Thr Ala Ile Tyr Cys Phe Leu Arg Cys Met Glu Pro His Pro Glu Ile   1 5 10 15 Pro Ser Thr Phe Asn Ser Leu Gln Arg              20 25 <210> 109 <211> 15 <212> PRT <213> Mus musculus <400> 109 Ile Gln Gln Glu Ile Ala Val Gln Asn Pro Leu Val Ser Glu Arg   1 5 10 15 <210> 110 <211> 8 <212> PRT <213> Mus musculus <400> 110 Leu Glu Leu Ser Val Leu Tyr Lys   1 5 <210> 111 <211> 12 <212> PRT <213> Mus musculus <400> 111 Glu Tyr Ala Glu Asp Asp Asn Ile Tyr Gln Gln Lys   1 5 10 <210> 112 <211> 19 <212> PRT <213> Mus musculus <400> 112 Ala Phe Gly Phe Ser His Leu Glu Ala Leu Leu Asp Asp Ser Lys Glu   1 5 10 15 Leu Gln Arg             <210> 113 <211> 31 <212> PRT <213> Mus musculus <400> 113 Ser Lys Glu Asp Leu Val Ser Gln Gly Phe Thr Glu Phe Thr Ile Glu   1 5 10 15 Asp Phe His Asn Thr Phe Met Asp Leu Ile Glu Gln Val Glu Lys              20 25 30 <210> 114 <211> 9 <212> PRT <213> Mus musculus <400> 114 Leu Leu Thr Ser Gly Tyr Leu Gln Arg   1 5 <210> 115 <211> 13 <212> PRT <213> Mus musculus <400> 115 Glu Ser Lys Phe Phe Glu His Phe Ile Glu Gly Gly Arg   1 5 10 <210> 116 <211> 11 <212> PRT <213> Mus musculus <400> 116 Ser Val Ser Ile Gln Val Glu Tyr Met Asp Arg   1 5 10 <210> 117 <211> 18 <212> PRT <213> Mus musculus <400> 117 Gly Glu Gly Gly Thr Thr Asn Pro His Val Phe Pro Glu Gly Ser Glu   1 5 10 15 Pro Lys         <210> 118 <211> 15 <212> PRT <213> Mus musculus <400> 118 Val Tyr Leu Leu Tyr Arg Pro Gly His Tyr Asp Ile Leu Tyr Lys   1 5 10 15 <210> 119 <211> 8 <212> PRT <213> Mus musculus <400> 119 Asn Leu Leu Ser Val Ala Tyr Lys   1 5 <210> 120 <211> 12 <212> PRT <213> Mus musculus <400> 120 Tyr Leu Ile Leu Asn Ala Thr Gln Ala Glu Ser Lys   1 5 10 <210> 121 <211> 11 <212> PRT <213> Mus musculus <400> 121 Tyr Leu Ser Glu Val Ala Ser Gly Glu Asn Lys   1 5 10 <210> 122 <211> 20 <212> PRT <213> Mus musculus <400> 122 Lys Gln Thr Thr Val Ser Asn Ser Gln Gln Ala Tyr Gln Glu Ala Phe   1 5 10 15 Glu ile ser lys              20 <210> 123 <211> 19 <212> PRT <213> Mus musculus <400> 123 Thr Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Asn Glu Glu   1 5 10 15 Ser Tyr Lys             <210> 124 <211> 10 <212> PRT <213> Mus musculus <400> 124 Asp Ser Thr Leu Ile Met Gln Leu Leu Arg   1 5 10 <210> 125 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> forward primer for amplifying cDNA encoding ANF protein <400> 125 ggctccttct ccatcaccct g 21 <210> 126 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> reverse primer for amplifying cDNA encoding ANF protein <400> 126 tcttcggtac cggaagctgt t 21

Claims (6)

A biomarker for diagnosing myocardial hypertrophy, comprising one or more proteins selected from the following groups, wherein expression is relatively increased in cells that develop myocardial hypertrophy:
PDZ and LIM domain proteins having the amino acid sequence of SEQ ID NO: 1;
ADP-ribosylhydrolase having the amino acid sequence of SEQ ID NO: 2;
Peptidyl-prolyl cis-trans isomerase E having the amino acid sequence of SEQ ID NO: 3;
Translation elongation factor 1 delta isoform b of eukaryotic cells having the amino acid sequence of SEQ ID NO: 4;
Ran-specific GTPase-activating protein having the amino acid sequence of SEQ ID NO: 5;
ATP synthase subunit beta, mitochondrial precursor having the amino acid sequence of SEQ ID NO: 6; And
Isoform of Astrostatic Phosphoprotein PEA-15 Having the Amino Acid Sequence of SEQ ID NO: 7 A biomarker for diagnosing myocardial hypertrophy, comprising one or more proteins selected from the group below, wherein expression is relatively reduced in cells that develop myocardial hypertrophy:
Isoform C protein of Lamin-A / C having the amino acid sequence of SEQ ID NO: 8;
A 75 kDa heat shock protein having the amino acid sequence of SEQ ID NO: 9;
Heat shock 70 kDa protein 14 having the amino acid sequence of SEQ ID NO: 10;
FK506-binding protein 4 having the amino acid sequence of SEQ ID NO: 11;
Poly (ADP-ribose) glycohydrolase ARH3 having the amino acid sequence of SEQ ID NO: 12;
Ubiquitin thioesterase protein OTUB1 having the amino acid sequence of SEQ ID NO: 13; And
Isoform short 14-3-3 protein β / α having the amino acid sequence of SEQ ID NO: 14. Myocardial hypertrophy diagnostic kit comprising an antibody that specifically binds to a protein of claim 1 or a fragment of the protein. 4. The myocardial hypertrophy diagnostic kit according to claim 3, wherein the antibody is a monoclonal antibody. The expression of one or more of the proteins of claim 1 is increased relative to normal cardiomyocytes from a biological sample suspected of myocardial hypertrophy, or the expression of one or more of the proteins of claim 2 is relatively higher than that of normal cardiomyocytes. Detecting whether it decreases; And
Determining whether the biological sample is myocardial hypertrophy from the detection result. The method of claim 5, wherein the biological sample is myocardial tissue or cardiomyocytes of a mammal.

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