Physiological and functional effects of beta-cell-specific inactivation of the PGE2 receptor EP3

PGE2 受体 EP3 β 细胞特异性失活的生理和功能影响

• 批准号: 10248348
• 负责人: Ashley A Christensen
• 金额: $ 1.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248348
• 关键词: Ablation; Adenylate Cyclase; Adipose tissue; Adult; Affect; Age; American; B Cell Proliferation; Beta Cell; Binding; Brain; Cell Proliferation; Cell Survival; Cell physiology; Cessation of life; Couples; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Diet; Dinoprostone; FOXM1 gene; Failure; Fatty acid glycerol esters; Financial compensation; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Health; High Fat Diet; Human; Immune system; Impairment; Individual; Infiltration; Inflammation; Insulin; Insulin Resistance; Knockout Mice; Lead; Link; Lipids; Metabolic; Metabolic stress; Micronutrients; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pharmaceutical Preparations; Pharmacology; Physiological; Placental Lactogen; Play; Prostaglandin E Receptor; Protein Isoforms; Proteins; Public Health; Receptor Inhibition; Regulation; Risk Factors; Role; Signal Pathway; Signal Transduction; Stimulus; Structure of beta Cell of islet; Tissues; United States; Work; blood glucose regulation; cell regeneration; cell type; cohort; diabetic; dietary control; exhaustion; experimental study; feeding; improved; in vivo; insulin secretion; islet; macrophage; mouse model; necrotic tissue; overexpression; prevent; promoter; receptor; response; single-cell RNA sequencing; tool; transcription factor

Project summary/Abstract Type 2 diabetes is a major health concern in the United States. It occurs when individuals fail to compensate for an increased demand for insulin from the pancreatic β cells. The prostaglandin E receptor EP3 (encoded by Ptger3), which responds to prostaglandin E2 (PGE2), has been shown to inhibit insulin secretion. EP3 is upregulated in diabetic individuals and with age. Data from our lab has demonstrated that ex vivo pharmacological inhibition of EP3 increases β cell mass and survival. The role of EP3 specifically in the β cell has not been examined. I propose using a β-cell-specific EP3 KO mouse model to determine the effect of EP3 inactivation in the context of high fat diet. In addition, FoxM1 is a transcription factor necessary for β cell proliferation. FoxM1 levels decrease with age while EP3 levels increase. In this proposal, I outline experiments to elucidate what role, if any, FoxM1 has in regulating Ptger3 expression.

项目概要/摘要 2型糖尿病在美国是一个主要的健康问题。它发生在个人无法补偿 胰腺β细胞对胰岛素的需求增加。前列腺素E受体EP 3（由 对前列腺素E2（PGE 2）有反应的Ptger 3）已被证明能抑制胰岛素分泌。EP 3是 在糖尿病个体中随着年龄的增长而上调。我们实验室的数据表明， EP 3的药理学抑制增加β细胞质量和存活。EP 3在β细胞中的作用 还没有被检查。我建议使用β细胞特异性EP 3 KO小鼠模型来确定EP 3的作用。 在高脂肪饮食的情况下失活。此外，FoxM 1是β细胞所必需的转录因子， 增殖FoxM 1水平随着年龄的增长而下降，而EP 3水平则随着年龄的增长而增加。在这个建议中，我概述了实验 阐明FoxM 1在调节Ptger 3表达中的作用。