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Manipulating islet GPCR activity to promote beta cell proliferation and survival

操纵胰岛 GPCR 活性促进 β 细胞增殖和存活

基本信息

批准号：
10022326
负责人：
Maureen A Gannon
金额：
$ 42.5万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022326
关键词：
Address Adult Age Agonist B Cell Proliferation Beta Cell Cell Death Cell Proliferation Cell Survival Cell physiology Coupled Cues Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Dinoprostone Disease FOXM1 gene Female G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Gestational Diabetes Goals Human Immunodeficient Mouse Impairment Incidence Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Kidney Mediating Mitogens Modeling Molecular Target Mus Non-Insulin-Dependent Diabetes Mellitus Outcome Pathway interactions Pharmacology Phosphoproteins Physiological Placental Lactogen Population Predisposition Regulation Signal Pathway Stimulus Streptozocin Testing WFDC2 gene blood glucose regulation capsule cell dedifferentiation db/db mouse design improved in vivo insulin secretion islet male mouse model new therapeutic target overexpression phospholipase C gamma phosphoproteomics preservation prevent receptor response tool transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract T2D incidence increases with age, in part due to a decreased ability of β cells to respond to proliferative cues as they get older. Our lab identified the FoxM1 transcription factor as a critical regulator of β-cell replication and survival. Foxm1 expression in islets declines with age in mice and humans, but activation of FoxM1 in older mouse β cells increases β- cell proliferation and mass. RNA-sequencing revealed that FoxM1 over-expression in β cells decreases expression of EP3 and increases expression of EP4, two G protein- coupled prostaglandin E2 (PGE2) receptors. In isolated islets from mouse and human, we found that pharmacological inhibition of EP3 or activation of EP4 promotes β-cell proliferation and survival. The current proposal makes use of in vivo mouse models, human islet transplants and ex vivo islet cultures from humans with normoglycemia and Type 2 diabetes to determine the downstream signaling pathways that mediate the effects of inhibiting EP3 or activating EP4. Using phosphoprotein arrays of ex vivo treated mouse islets, we identified PLCγ and PKA as acting downstream of EP3 inhibition or EP4 activation, respectively. In the current proposal we explore the hyopothesis that EP3 blockade (working through PLCγ) or EP4 activation (working through PKA) will ameliorate diabetes and enhance human islet transplantation in vivo by increasing insulin secretion, and enhancing β-cell proliferation and survival. We propose that FoxM1 directly activates EP4 while repressing EP3 expression. These studies are designed to identify molecular targets to enhance function, proliferation and survival of β cells with the goal of increasing functional β cell mass.

项目概要/摘要 T2D 发病率随着年龄的增长而增加，部分原因是 β 细胞的反应能力下降随着年龄的增长，它们会受到增殖信号的影响。我们的实验室将 FoxM1 转录因子鉴定为 β细胞复制和存活的关键调节因子。胰岛中 Foxm1 表达下降在小鼠和人类中，随着年龄的增长，但老年小鼠 β 细胞中 FoxM1 的激活会增加 β- 细胞增殖和质量。 RNA测序显示FoxM1在β中过度表达细胞减少 EP3 的表达并增加 EP4 的表达，这两种 G 蛋白 - 耦合前列腺素 E2 (PGE2) 受体。在小鼠和人类的孤立胰岛中，我们发现药理学抑制 EP3 或激活 EP4 可促进 β 细胞增殖和生存。目前的提案利用体内小鼠模型，人类胰岛移植和来自血糖正常的人类的离体胰岛培养物 2 型糖尿病以确定介导影响的下游信号通路抑制EP3或激活EP4。使用离体处理小鼠的磷蛋白阵列在胰岛中，我们确定 PLCγ 和 PKA 发挥 EP3 抑制或 EP4 下游作用分别激活。在当前的提案中，我们探讨了 EP3 的假设封锁（通过 PLCγ 发挥作用）或 EP4 激活（通过 PKA 发挥作用）将改善糖尿病并通过增加胰岛素分泌来增强人体内胰岛移植，并增强β细胞增殖和存活。我们建议FoxM1直接激活 EP4同时抑制EP3表达。这些研究旨在识别分子目标是增强 β 细胞的功能、增殖和存活，从而增加功能性β细胞团。