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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.

摘要本申请响应RFA-RM-19-011，并将重点关注在糖尿病的背景下，阐明被称为GPR 31的可药用基因组（IDG）数据库。来在过去的十年里，我们的实验室一直专注于炎症和细胞对炎症的反应，导致β细胞功能障碍和死亡的中枢机制1型糖尿病（T1 D）和2型糖尿病（T2D）。具体来说，我们的实验室已经证明，12-脂氧合酶（12-LOX），一种参与花生四烯酸代谢并在β细胞中表达，在β细胞炎症的情况下被激活，产生类二十烷酸12-S-羟基二十碳四烯酸（12（S）-HETE）。12（S）-HETE生成内质网（ER）和β细胞中的氧化应激，但发生这种情况的机制仍然难以捉摸在小鼠中缺失编码12-LOX的基因（Alox 15），条件性地在胰岛中缺失或在全球范围内，导致NOD小鼠和肥胖诱导的2型糖尿病中自发性1型样糖尿病的保护，比如高脂肪喂养的老鼠患糖尿病。GPR 31最近被去孤儿化并被鉴定为12（S）-HETE 受体的我们通过传统的ES方法在C57 BL 6/J背景下产生了同源Gpr 31 b-/-小鼠细胞克隆初步数据表明，Gpr 31-/-小鼠是可行的，代谢正常，类似于Alox 15-/-小鼠。 /-小鼠，然而，仍有待确定GPR 31是否介导12-LOX在致糖尿病条件下的作用。 β细胞中的条件。在本提案中，我们将生成支持GPR 31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，将提供给资源传播和推广中心（RDOC）， IDG计划。这项拨款提案继续了S博士之间长期和富有成效的合作。 Tersey和R. Mirmira，他们在芝加哥大学共同工作。结合博士的专业知识。 Mirmira在β细胞信号级联和Tersey博士在糖尿病动物模型中的协同作用，完成这一试点工作。我们的团队将测试GPR 31促进β细胞炎症的假设。在糖尿病的情况下，β-细胞信号传导并导致β-细胞功能障碍和死亡。为了验证这一假设，将在本区域渔业协定规定的时限内实现以下两个目标：目的1：阐明GPR 31在介导糖尿病性炎症中的作用和12（S）-HETE在小岛目的2：表征GPR 31在正常和促炎条件下的体内代谢作用。该提案的主要影响是确定GPR 31是否是药物治疗的合适靶点。在糖尿病炎症的背景下发展。