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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：
10453748
负责人：
Maureen A Gannon
金额：
$ 42.44万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453748
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 antagonist 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.

项目摘要/摘要 T2D的发病率随着年龄的增长而增加，部分原因是β细胞的反应能力降低随着年龄的增长，对增殖的线索。我们实验室鉴定了FOXM1转录因子为 β的关键调节因子--细胞复制和存活。胰岛中FOXM1的表达下降在小鼠和人中，随着年龄的增长，但老年小鼠β细胞中FOXM1的激活增加了β- 细胞增殖和肿块。测序结果显示FOXM1在β中高表达细胞减少EP3的表达，增加EP4的表达，两种G蛋白- 偶联前列腺素E2(PGE2)受体。在与小鼠和人隔离的小岛上，我们发现药物抑制EP3或激活EP4促进β-细胞扩散和生存。目前的方案利用了活体小鼠模型，血糖正常的人胰岛移植和体外胰岛培养 2型糖尿病以确定调节其影响的下游信号通路抑制EP3或激活EP4。利用体外处理小鼠的磷化蛋白阵列胰岛，我们确定PLCγ和PKA在EP3抑制或EP4的下游起作用分别激活。在目前的提案中，我们探讨了EP3的下位封锁(通过可编程控制器γ)或EP4激活(通过PKA)将会改善糖尿病和通过增加胰岛素分泌来促进体内人类胰岛移植，并促进β-细胞的增殖和存活。我们认为FOXM1直接激活 EP4同时抑制EP3的表达。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，目标是增加功能性β细胞团。