The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage

溶血磷脂酸受体LPA5R在肠道炎症和上皮损伤中的作用

基本信息

批准号：
10163842
负责人：
Changhyon Chris Yun
金额：
$ 50.7万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163842
关键词：
Abnormal Cell Acute Affect Animals Apoptosis Apoptotic Atherosclerosis Brush Border Cell Death Cell Survival Colitis Colonic Neoplasms Colorectal Cancer Country Crohn&apos s disease Data Defect Development Disease Enterocolitis Environment Epithelial Epithelial Attachment Epithelial Cells Family Financial Hardship Functional disorder Future G-Protein-Coupled Receptors GPR35 gene Gastrointestinal tract structure Homeostasis Inflammatory Bowel Diseases Injury Interleukin-1 beta Intestines Ionizing radiation Knock-out Knockout Mice Lead Ligands Link Lipids Lysophosphatidic Acid Receptors Maintenance Malignant Neoplasms Mammals Mediating Modeling Morbidity - disease rate Mucosal Immunity Mus Natural regeneration Neoplasms Organism Paneth Cells Pathogenesis Pathologic Permeability Predisposition Recovery Regulation Resistance Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Stress Suggestion TNF gene Tamoxifen Testing Ulcerative Colitis United States Villus Work cell regeneration cell type crypt cell cytokine cytotoxicity dextran sulfate sodium induced colitis epithelial injury epithelial repair factor A genome wide association study human disease inflammatory disease of the intestine intestinal crypt intestinal epithelium intestinal villi lysophosphatidic acid mouse model novel prevent protein expression receptor receptor function response stem cell survival stem cells tumor growth

项目摘要

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, affects 1-2 million people in the United States, and is a significant financial burden for the country. IBD increases the risk factor for other diseases such as colorectal cancer and atherosclerosis. Intestinal epithelial cells (IECs) form the physical barrier that protects the body from the hostile environment of the gut, and damage to the intestinal epithelium leads to the entry of noxious molecules and organisms, which activates the mucosal immunity. Lysophosphatidic acid (LPA), a naturally occurring bioactive lipid, acts on a family of G protein-coupled receptors to mediate multiple effects that can regulate survival and proliferation of various cell types. Of six known LPA receptors, LPA5R is highly expressed in the gastrointestinal (GI) tract. A recent genome-wide association study (GWAS) for early on- set of IBD identified a single nucleotide polymorphism within the GPCR GPR35. A subsequent study has shown that LPA is an endogenous ligand of GPR35, linking aberrant LPA-mediated signaling to the pathogenesis of IBD. Significant expression of LPA5R in the GI tract and the suggestion of aberrant LPA-mediated signaling prompted us to generate a novel mouse model in which LPA5R can be deleted inducibly or constitutively. Preliminary studies show that inducible deletion of LPA5R resulted in crypt IEC apoptosis, severe colitis, and increased morbidity, without visible effects on villus IECs. In contrast, mice with constitutive deletion of LPA5R appear normal, suggesting compensatory protection. Surprisingly, we found that crypt epithelial cells with constitutive deletion of LPA5R are more resistant to ionizing radiation- or cytokine-induced apoptosis, suggesting overcompensated cell survival. However, both constitutive and inducible deletion resulted in increased epithelial permeability and decreased epithelial junctional protein expression in villus epithelium, suggesting that LPA5R regulates epithelial barrier function. We hypothesize that LPA5R maintains the integrity of intestinal epithelium by regulating survival of crypt epithelial cells and the epithelial barrier functions at the brush border. We will investigate the underlying cause of IEC death upon LPA5R deletion and the role of LPA5R in IEC regeneration (aim 1). We will determine the underlying mechanism for the compensatory increase in IEC survival in constitutive deletion and test the hypothesis that overcompensated crypt cell survival promotes survival of abnormal cells in response to stress (aim 2). Additionally, we will investigate that epithelial barrier dysfunction in the absence of LPA5R that elevates intestinal inflammation and, together with increased IEC survival, increases the susceptibility to colon neoplasia (aim 3). The proposed studies should reveal the novel functions of LPA5R in the maintenance of intestinal epithelium. We anticipate that successful completion of this study will identify LPA5R as a key regulator of epithelial repair and colonic neoplasia, and the findings generated from these studies will have significant translational potential that may eventually be extended to human disease in the future.

炎症性肠病 (IBD)，包括克罗恩病和溃疡性结肠炎，影响着 1-200 万人 IBD 给美国带来了沉重的财政负担，增加了其他国家的风险因素。肠上皮细胞（IEC）形成了物理屏障，例如结直肠癌和动脉粥样硬化。保护身体免受肠道恶劣环境的影响，而肠上皮的损伤会导致有毒分子和生物体的进入，激活粘膜免疫。 (LPA) 是一种天然存在的生物活性脂质，作用于 G 蛋白偶联受体家族，介导多种在六种已知的 LPA 受体中，LPA5R 具有调节多种细胞类型存活和增殖的作用。最近的一项针对早期的全基因组关联研究（GWAS）在胃肠道（GI）中高表达。随后的研究表明，IBD 组在 GPCR GPR35 内发现了一个单核苷酸多态性。 LPA 是 GPR35 的内源性配体，将异常的 LPA 介导的信号传导与 GPR35 的发病机制联系起来 IBD。LPA5R 在胃肠道中的显着表达以及 LPA 介导的信号传导异常的提示促使我们生成一种新的小鼠模型，其中 LPA5R 可以诱导性或组成性删除。初步研究表明，LPA5R 的诱导缺失会导致隐窝 IEC 细胞凋亡、严重结肠炎和发病率增加，但对绒毛 IEC 没有明显影响，相比之下，LPA5R 组成型缺失的小鼠。看起来正常，表明有代偿性保护，我们发现隐窝上皮细胞具有代偿性保护。 LPA5R 的组成型缺失更能抵抗电离辐射或细胞因子诱导的细胞凋亡，这表明然而，组成型和诱导型缺失都会导致上皮细胞存活率增加。绒毛上皮的通透性和上皮连接蛋白表达降低，表明 LPA5R 我们相信 LPA5R 可以维持肠上皮的完整性。通过调节隐窝上皮细胞的存活和刷状缘的上皮屏障功能。研究 LPA5R 缺失导致 IEC 死亡的根本原因以及 LPA5R 在 IEC 再生中的作用（目标 1）我们将确定 IEC 生存补偿性增加的基本机制。组成型缺失并检验过度补偿的隐窝细胞存活促进存活的假设此外，我们将研究上皮屏障功能障碍。 LPA5R 的缺乏会加剧肠道炎症，并与 IEC 存活率增加一起，增加对结肠肿瘤的易感性（目标 3）。拟议的研究应揭示 LPA5R 的新功能。我们预计这项研究的成功完成将确定 LPA5R 作为上皮修复和结肠肿瘤的关键调节因子，以及由此产生的发现研究将具有巨大的转化潜力，最终可能扩展到人类疾病未来。