CN118546881A - Il-1rl1刺激剂在制备上调动物细胞中fam134b表达水平的试剂中的应用 - Google Patents
Il-1rl1刺激剂在制备上调动物细胞中fam134b表达水平的试剂中的应用 Download PDFInfo
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Abstract
本发明公开了IL‑1RL1刺激剂在制备上调动物细胞中FAM134B表达水平的试剂中的应用，属于生物医学领域。本发明通过研究IL‑1RL1刺激剂白细胞介素33(IL‑33)对动物细胞中FAM134B表达水平的影响，发现IL‑33能够上调动物细胞中FAM134B表达水平。IL‑1RL1刺激剂可用于制备上调动物细胞中FAM134B表达水平的试剂。
Description
技术领域
本发明是属于生物医学领域，特别是关于IL-1RL1刺激剂在制备上调动物细胞中FAM134B表达水平的试剂中的应用。
背景技术
序列相似性家族134成员B(family with sequence similarity 134,member B，FAM134B)，又名RETREG1(reticulophagy regulator 1)，2001年作为癌基因在食管鳞状细胞癌中被发现，2015年被证实为一种非常重要的内质网选择性自噬受体。该蛋白主要定位于内质网的片状结构，有两个重要的结构域：微管相关蛋白1轻链3(LC3)结合结构域(LIR)和网织体同源结构域(RHD)。LIR负责与自噬体结合，而RHD则感知并诱导内质网膜弯曲。FAM134B介导的内质网自噬在许多疾病中发挥着极其关键的作用，包括神经系统疾病、消化系统疾病、心血管疾病、感染性疾病和肿瘤等。FAM134B强大的生物学效应正逐渐得以揭示，研究FAM134B的调控机制和策略，无论在理论研究层面，还是在实际应用层面，均具有重要意义。
公开于该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不应当被视为承认或以任何形式暗示该信息构成已为本领域一般技术人员所公知的现有技术。
发明内容
本发明通过研究IL-1RL1刺激剂白细胞介素33(IL-33)对动物细胞中FAM134B表达水平的影响，发现IL-1RL1刺激剂能够通过其特异性受体IL-1RL1上调动物细胞中FAM134B表达水平。
本发明第一方面提供IL-1RL1刺激剂在制备上调动物细胞中FAM134B表达水平的试剂中的应用。
在本发明的一实施方式中，所述动物为哺乳动物。
在本发明的一实施方式中，所述细胞为树突状细胞(DCs)。
本发明第二方面提供一种上调动物细胞中FAM134B表达水平的方法，包括向动物细胞施用含有IL-1RL1刺激剂的试剂。
本发明第三方面提供IL-1RL1刺激剂在制备治疗FAM134B相关疾病的药物中的应用。
在本发明的一实施方式中，所述IL-1RL1刺激剂为白细胞介素33(IL-33)。
在本发明的一实施方式中，IL-33的浓度优选为1～10ng/ml。
在本发明的一实施方式中，所述FAM134B相关疾病选自神经系统疾病、消化系统疾病、心血管疾病、感染性疾病和肿瘤。
在本发明的一实施方式中，所述神经系统疾病为阿尔茨海默病、帕金森病或亨廷顿病。
在本发明的一实施方式中，所述心血管疾病为心肌梗死或心力衰竭。
在本发明的一实施方式中，所述感染性疾病为脓毒症。
本发明提及的哺乳动物可为任何哺乳动物，包括但不限于啮齿目动物、兔形目动物、偶蹄目动物、奇蹄目动物、灵长目动物、食肉目动物。啮齿目动物包括但不限于鼠科动物(小鼠、大鼠)和仓鼠科动物(仓鼠)。兔形目动物包括但不限于兔科动物(兔)。偶蹄目动物包括但不限于牛科动物(牛、羊)和猪科动物(猪)。奇蹄目动物包括但不限于马科动物(马)。灵长目动物包括但不限于猴科(猕猴)、长臂猿科(长臂猿)、人科(人、黑猩猩)。优选的，哺乳动物为啮齿目动物或灵长目动物。特别优选的哺乳动物为人。
本发明的药物可以通过本领域任何已知的方式配制药物组合物来使用。这种组合物包含活性成分，加上一种或多种药物可接受的载体、稀释剂、填充剂、结合剂及其它赋形剂，这依赖于给药方式及所设计的剂量形式。本领域枝术人员已知的治疗惰性的无机或有机的载体包括(但不限于)乳糖、玉米淀粉或其衍生物、滑石、植物油、蜡、脂肪、多羟基化合物例如聚乙二醇、水、蔗糖、乙醇、甘油，诸如此类，各种防腐剂、润滑剂、分散剂、矫味剂。保湿剐、抗氧化剂、甜味剂、着色剂、稳定剂、盐、缓冲液诸如此类也可加入其中，这些物质根据需要用于帮助配方的稳定性或有助于提高活性或它的生物有效性或在口服的情况下产生可接受的口感或气味，在这种组合物中可以使用的制剂可是其原始化合物本身的形式，或任选地使用其药物学可接受的盐的形式，本发明的药物可以单独给药，或以各种组合给药，以及与其它治疗药剂一起结合形式给药。如此配制的组合物根据需要可选择本领域技术人员已知的任何适当的方式把药物进行给药。使用药物组合物时，是将安全有效量的本发明的药物施用于人，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的药物可根据需要制备成各种剂型。包括但不限于，经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
本发明的药物的施用途径不受限制，只要它能发挥期望的治疗效果或预防效果即可，包括但不限于静脉内，腹膜内，眼内，动脉内，肺内，口服，小泡内，肌肉内，气管内，皮下的，通过皮肤，通过胸膜，局部的，吸入，通过粘膜，皮肤，肠胃，关节内，心室内，直肠，阴道，颅骨内，尿道内，肝内，瘤内。在某些情况下，可以系统地给药。在某些情况下是局部地给药。
本发明的药物的剂量不受限制，只要获得期望的治疗效果或者预防效果即可。本发明的治疗药物或预防药物的剂量可以使用例如对疾病的治疗效果或者预防效果作为指标来确定。
本文所用的“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态，并且包括：
(1)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(2)抑制疾病或疾病状态，即阻止其发生；或者
(3)缓解疾病或疾病状态，即使疾病或疾病状态消退。
附图说明
图1是野生型(WT)小鼠与Il33-/-小鼠盲肠结扎穿刺法(CLP)术后脾脏DCs胞内FAM134B蛋白相对表达水平对比图；
图2是WT小鼠与Il33-/-小鼠CLP术后脾脏DCs胞内FAM134B蛋白表达水平统计图；
图3是野生型(WT)小鼠与Il1rl1-/-小鼠CLP术后脾脏DCs胞内FAM134B蛋白表达水平对比图；
图4是WT小鼠与Il1rl1-/-小鼠CLP术后脾脏DCs胞内FAM134B蛋白相对表达水平统计图；
图5是IL-33刺激后不同时间野生型小鼠脾脏DCs胞内FAM134B蛋白表达水平对比图；
图6是IL-33刺激后不同时间野生型小鼠脾脏DCs胞内FAM134B蛋白相对表达水平统计图；
图7是IL-33刺激后24小时WT小鼠与Il1rl1-/-小鼠脾脏DCs胞内FAM134B蛋白表达水平对比图；
图8是IL-33刺激后24小时WT小鼠与Il1rl1-/-小鼠脾脏DCs胞内FAM134B蛋白相对表达水平统计图。
具体实施方式
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
以下通过具体实施例说明本发明的技术方案。应该理解，本发明提到的一个或者多个步骤不排斥在组合步骤前后还存在其他方法和步骤，或者这些明确提及的步骤间还可以插入其他方法和步骤。还应理解，这些实例仅用于说明本发明而不用于限制本发明的范围。除非另有说明，各方法步骤的编号仅为鉴别各方法步骤的目的，而非限制每个方法的排列次序或限定本发明的实施范围，其相对关系的改变或调整，在无实质技术内容变更的条件下，亦可视为本发明可实施的范畴。
实施例中所采用的原料和仪器，对其来源没有特定限制，在市场购买或者按照本领域内技术人员熟知的常规方法制备即可。
盲肠结扎穿刺法(CLP)脓毒症小鼠模型体内FAM134B表达情况的对比研究
利用基因操作手段敲除小鼠IL-33及其特异性受体IL-1RL1基因，获得IL-33基因敲除小鼠(Il33-/-)和IL-1RL1基因敲除(Il1rl1-/-)小鼠。野生型(WT)小鼠、Il33-/-小鼠及Il1rl1-/-小鼠行盲肠结扎穿孔术构建脓毒症模型，术后24小时提取脾脏DCs细胞样本，利用Western Blot实验检测细胞内FAM134B蛋白水平变化，检测结果见图1、图2、图3、图4。经ImageJ软件分析蛋白条带灰度值，结果显示：IL-33基因敲除后，CLP脓毒症小鼠脾脏DCs胞内FAM134B表达水平明显较WT小鼠偏低(见图1、图2，P<0.01)，说明IL-33是诱导FAM134B表达升高的关键因素。另外，IL-33的特异性受体IL-1RL1基因敲除的CLP脓毒症小鼠，其脾脏DCs胞内FAM134B表达水平较WT小鼠亦明显偏低(见图3、图4，P<0.01)，说明IL-33通过受体IL-1RL1激活下游信号通路调控FAM134B表达。上述结果提示，IL-33/IL-1RL1信号轴是介导FAM134B蛋白上调的重要机制。
IL-1RL1刺激剂IL-33刺激与FAM134B表达水平之间关系的研究
为进一步验证IL-1RL1刺激剂IL-33对FAM134B表达的直接诱导效应，我们分离纯化野生型正常小鼠脾脏DCs，体外培养并给予重组IL-33(10ng/ml)刺激，于刺激后预定时间(6h、12h、24h、48h、72h)收集细胞样本，利用Western Blot实验检测细胞内蛋白水平变化，条带灰度值经ImageJ软件提取，以内参β-actin蛋白条带灰度值为基准对FAM134B蛋白条带灰度值进行量化统计分析，检测结果见图5和图6。检测结果表明：IL-33刺激12h后DCs胞内FAM134B相对表达水平出现显著升高趋势，刺激后24h较对照组明显上升，之后到72小时FAM134B蛋白一直维持在较高表达水平，提示IL-33可介导FAM134B表达上调。(说明：在预实验中，分别以1ng/ml、10ng/ml、100ng/ml的不同浓度的IL-33对小鼠脾脏DCs进行刺激，不同浓度IL-33均可上调FAM134B蛋白表达水平，其中1ng/ml组与10ng/ml组组间对比无统计学差异(P>0.05)，100ng/ml组与10ng/ml组相比上调水平偏低(P<0.01)，所以，IL-33的浓度优选为1～10ng/ml，在本申请中，均以10ng/ml浓度的IL-33进行实验)。**表示与对照组相比P<0.01。
进一步分离纯化正常野生型(WT)小鼠、Il1rl1-/-小鼠脾脏DCs，体外培养并分别给予重组IL-33(10ng/ml)刺激，刺激后24h收集细胞样本，利用Western Blot实验检测细胞内蛋白水平变化，检测结果见图7和图8。经ImageJ软件分析蛋白条带灰度值，结果显示：Il1rl1-/-组IL-33刺激诱导FAM134B蛋白表达水平升高的效果大幅度减小，Il1rl1-/--IL-33-24h组明显较WT-IL-33-24h组偏低(P<0.01)。说明给予重组IL-33刺激不能在Il1rl1-/-小鼠脾脏DCs中诱导FAM134B蛋白表达量上调，证明IL-33上调FAM134B蛋白表达的生物学效应与其特异性受体IL-1RL1有关。即，IL-33是作为IL-1RL1的刺激剂发挥作用的。从机理上说，任何能够与IL-1RL1特异性结合并激活IL-1RL1的刺激剂均可发挥诱导FAM134B蛋白表达量上调的作用。
研究表明，FAM134B蛋白表达水平低下对许多疾病起着促进作用，与神经系统疾病、消化系统疾病、心血管疾病、感染性疾病、肿瘤等疾病的进展有关。而IL-33或其他IL-1RL1刺激剂能够上调FAM134B蛋白表达水平，因此，IL-33或其他IL-1RL1刺激剂有望用于在制备治疗FAM134B相关疾病的药物。所述FAM134B相关疾病为神经系统疾病、消化系统疾病、心血管疾病、感染性疾病、肿瘤等疾病中的一种或多种。所述神经系统疾病为阿尔茨海默病、帕金森病和亨廷顿病中的一种或多种。所述心血管疾病为心肌梗死或心力衰竭。所述感染性疾病为脓毒症。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
Claims (10)
1.IL-1RL1刺激剂在制备上调动物细胞中FAM134B表达水平的试剂中的应用。
2.根据权利要求1所述的应用，其特征在于，所述动物为哺乳动物。
3.根据权利要求1所述的应用，其特征在于，所述细胞为树突状细胞。
4.一种上调动物细胞中FAM134B表达水平的方法，其特征在于，包括向动物细胞施用含有IL-1RL1刺激剂的试剂。
5.IL-1RL1刺激剂在制备治疗FAM134B相关疾病的药物中的应用。
6.根据权利要求1或5所述的应用或者权利要求4所述的方法，其特征在于，所述IL-1RL1刺激剂为白细胞介素33。
7.根据权利要求5所述的应用，其特征在于，所述FAM134B相关疾病选自神经系统疾病、消化系统疾病、心血管疾病、感染性疾病和肿瘤。
8.根据权利要求7所述的应用，其特征在于，所述神经系统疾病为阿尔茨海默病、帕金森病或亨廷顿病。
9.根据权利要求7所述的应用，其特征在于，所述心血管疾病为心肌梗死或心力衰竭。
10.根据权利要求7所述的应用，其特征在于，所述感染性疾病为脓毒症。
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