The 12-HETE receptor Gpr31 in the -cell pathogenesis of type 1 diabetes

12-HETE 受体 Gpr31 在 1 型糖尿病细胞发病机制中的作用

基本信息

批准号：
10047529
负责人：
Raghavendra G Mirmira
金额：
$ 16.2万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047529
关键词：
12-HETE Adult Animal Model Applications Grants Arachidonate 12-Lipoxygenase Arachidonic Acids Beta Cell Cells Cessation of life Chicago Clone Cells Collaborations Data Data Set Diabetes Mellitus Disease Drug Targeting Eicosanoids Endoplasmic Reticulum Enzymes Fatty acid glycerol esters Female Functional disorder G-Protein-Coupled Receptors GPR31 receptor Gene Deletion Genetic Genome Hydroxyeicosatetraenoic Acids Inbred NOD Mice Individual Inflammation Inflammation Mediators Inflammatory Insulin Insulin-Dependent Diabetes Mellitus LOX gene Laboratories Link Mediating Metabolic Metabolism Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Orphan Oxidative Stress Pathogenesis Phenotype Positioning Attribute Reagent Research Proposals Resources Role Signal Transduction Streptozocin Testing Tissues Universities base blood glucose regulation congenic cytokine data resource data to knowledge diabetic diabetogenic drug development embryonic stem cell experimental study genome database genomic data impaired glucose tolerance in vivo islet knowledge base male novel outreach programs receptor response transcriptome transcriptomics type I and type II diabetes virtual

项目摘要

Abstract This application is responsive to RFA-RM-19-011 and will focus on a poorly characterized GPCR in the Illuminating the Druggable Genome (IDG) database known as GPR31 in the context of diabetes. Over the past decade, our laboratory has focused on inflammation and the cellular response to inflammation as a central mechanism that contributes to β-cell dysfunction and death type 1 diabetes (T1D) and type 2 diabetes (T2D). Specifically, our laboratory has demonstrated that 12-lipoxygenase (12-LOX), an enzyme involved in arachidonic acid metabolism and expressed in β-cells, is activated in the context of β-cell inflammation and produces the eicosanoid 12-S-hydroxyeicosatetraenoic acid (12(S)-HETE). 12(S)-HETE generates endoplasmic reticulum (ER) and oxidative stress in β cells, but the mechanism through which this occurs has remained elusive. Deletion of the gene encoding 12-LOX in mice (Alox15), either conditionally in islets or globally, leads to protection from spontaneous type 1-like diabetes in NOD mice and obesity-induced type 2- like diabetes in high fat-fed mice. GPR31 has recently been de-orphaned and identified as the 12(S)-HETE receptor. We have generated congenic Gpr31b-/- mice on the C57BL6/J background through traditional ES cell cloning. Preliminary data suggest that Gpr31-/- mice are viable and metabolically normal, similar to Alox15- /- mice, however it remains to be determined if GPR31 mediates the effects of 12-LOX under diabetogenic conditions in β-cells. In this proposal, we will generate preliminary data supporting the potential role of GPR31 as a key mediator of inflammation-induced β-cell dysfunction and death, and the data and resources generated from this proposal will be made available to the Resource Dissemination and Outreach Center (RDOC) of the IDG program. This grant proposal continues a longstanding and productive collaboration between Drs. S. Tersey and R. Mirmira, who are co-located at the University of Chicago. The combined expertise of Dr. Mirmira in β cell signaling cascades and Dr. Tersey in animal models of diabetes are synergistic towards the completion of this pilot proposal. Our Team will test the hypothesis that GPR31 promotes β-cell inflammatory signaling and contributes to β-cell dysfunction and death in the setting of diabetes. To test this hypothesis, the following two aims will be achieved within the timeframe allotted to this RFA: Aim 1: Elucidate the role of GPR31 in mediating the effects of diabetogenic inflammation and 12(S)-HETE in islets. Aim 2: Characterize the metabolic effects of GPR31 in vivo under normal and pro-inflammatory conditions. The primary impact of this proposal is the determination of whether GPR31 is a suitable target for drug development in the context of diabetic inflammation.

抽象的该应用程序响应 RFA-RM-19-011，并将重点关注在糖尿病背景下阐明可药物基因组 (IDG) 数据库（GPR31）。在过去的十年中，我们的实验室一直专注于炎症和细胞对炎症的反应作为导致 β 细胞功能障碍和死亡 1 型糖尿病 (T1D) 和 2 型糖尿病的核心机制 (T2D) 具体而言，我们的实验室已证明 12-脂氧合酶 (12-LOX) 是一种参与的酶。花生四烯酸代谢并在 β 细胞中表达，在 β 细胞炎症和产生类二十烷酸 12-S-羟基二十碳四烯酸 (12(S)-HETE)。 β细胞中的内质网（ER）和氧化应激，但其发生的机制尚未确定小鼠中编码 12-LOX 的基因（Alox15）的删除仍然难以捉摸，无论是在胰岛中还是在有条件的情况下。在全球范围内，可预防 NOD 小鼠自发性 1 型糖尿病和肥胖引起的 2 型糖尿病就像高脂肪喂养的小鼠中的糖尿病一样，GPR31 最近已被鉴定为 12(S)-HETE。我们通过传统的 ES 在 C57BL6/J 背景上生成了同源 Gpr31b-/- 小鼠。细胞克隆的初步数据表明，Gpr31-/- 小鼠能够存活且代谢正常，与 Alox15- 类似。 /- 小鼠，但 GPR31 是否介导 12-LOX 在致糖尿病情况下的作用仍有待确定在本提案中，我们将生成支持 GPR31 潜在作用的初步数据。作为炎症诱导的 β 细胞功能障碍和死亡的关键介质，以及产生的数据和资源该提案中的内容将提供给资源传播和外展中心（RDOC） IDG 计划继续了 S. Tersey 和 R. Mirmira 共同任职于芝加哥大学。 Mirmira 在 β 细胞信号级联中的作用和 Dr. Tersey 在糖尿病动物模型中的作用具有协同作用完成该试点提案后，我们的团队将测试 GPR31 促进 β 细胞炎症的假设。信号传导并导致糖尿病背景下的 β 细胞功能障碍和死亡。以下两个目标将在本次 RFA 规定的时间内实现：目标 1：阐明 GPR31 在介导糖尿病性炎症和 12(S)-HETE 的作用中的作用胰岛。目标 2：表征正常和促炎条件下 GPR31 体内的代谢作用。该提案的主要影响是确定GPR31是否是合适的药物靶点糖尿病炎症背景下的发展。