Pathways regulating adult pancreatic beta cell replication

调节成人胰腺β细胞复制的途径

• 批准号: 9241554
• 负责人: Maureen A Gannon
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241554
• 关键词: Ablation; Address; Adult; Affect; Age; B Cell Proliferation; Beta Cell; Biochemical; Bypass; Cell Death; Cell Survival; Cell physiology; Cells; Couples; Cues; Data; Diabetes Mellitus; Dinoprostone; Disease; EP4 receptor; FOXM1 gene; Failure; Female; G-substrate; GTP-Binding Proteins; Genetic; Gestational Diabetes; Glucose; Goals; Growth Factor; High Fat Diet; Human; Impairment; Incidence; Insulin Resistance; Integrin alpha5beta1; Integrins; Lead; Link; Mediating; Molecular Target; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmacology; Play; Population; Pregnancy loss; Prostaglandin E Receptor; Prostaglandin Receptor; Prostaglandins; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Structure of beta Cell of islet; Testing; Treatment Factor; Veterans; WFDC2 gene; Winged Helix; age related; cell injury; cell type; chemokine; connective tissue growth factor; cytokine; design; impaired glucose tolerance; in vivo; insulin secretion; interest; islet; macrophage; male; mouse model; new therapeutic target; novel; postnatal; receptor; response; transcription factor

Project Summary/Abstract Type 2 diabetes (T2D) disproportionately affects the Veteran population: while 9% percent of the total US population has T2D, 25% of the Veteran population suffers from this disease. Adult β cell mass normally increases via replication in response to insulin resistance, but failure of β cell proliferation plus increased β cell death lead to T2D. 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 postnatal β cell replication and discovered that it is induced in response to several β cell proliferative stimuli. 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 β cell mass, while enhancing β cell function. Thus, our data demonstrate that FoxM1 is limiting in older β cells and that activating FoxM1 can bypass inherent brakes in β cell proliferation. Little is known about how proliferative stimuli induce Foxm1. Our lab discovered that connective tissue growth factor (CTGF) induces Foxm1 and adult β cell proliferation in mouse islets in vivo and ex vivo and in human islets ex vivo. The mechanisms and signaling pathways through which CTGF has these effects are currently unknown This study makes use of unique in vivo mouse models as well as ex vivo studies in both mouse and human islets from different ages. In this proposal we will identify and manipulate CTGF signaling pathways in β cells as molecular targets for enhancing proliferation and regeneration in adult β cells. In addition, we explore mechanisms through which FoxM1 activation enhances β cell proliferation and survival, focusing on the antagonistic prostaglandin E receptors EP3 and EP4, which are reciprocally regulated by FoxM1 in islets. We hypothesize that CTGF acts through integrin β1 signaling to induce Foxm1 expression and adult β cell proliferation, and that in the setting of β cell death, CTGF function is enhanced by macrophage-derived signals. We further hypothesize that FoxM1 activation overcomes age-related changes in β cell proliferation in part through alterations in prostaglandin receptor activity. In this proposal we will: 1) Identify signaling pathways through which CTGF activates Foxm1 expression and β cell proliferation; 2) Identify macrophage- derived factors that cooperate with CTGF to enhance β cell mass regeneration; and 3) Determine the role of prostaglandin EP receptors in β cell proliferation and survival. These studies are designed to identify molecular targets to enhance proliferation and survival in older β cells with the goal of increasing functional β cell mass.

项目概要/摘要 2 型糖尿病 (T2D) 对退伍军人群体的影响尤为严重：而 9% 占美国总人口的 25% 患有 T2D，25% 的退伍军人患有 T2D 这种病。成人 β 细胞质量通常会通过复制来响应胰岛素而增加 抵抗，但 β 细胞增殖失败加上 β 细胞死亡增加会导致 T2D。 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，会出现增殖迹象。我们的实验室将 FoxM1 转录因子鉴定为 出生后 β 细胞复制的关键调节因子，并发现它是在 对多种β细胞增殖刺激的反应。 Foxm1 在胰岛中的表达随 小鼠和人类的年龄，但老年小鼠 β 细胞中 FoxM1 的激活会增加 β 细胞 增殖和β细胞质量，同时增强β细胞功能。因此，我们的数据 证明 FoxM1 在较老的 β 细胞中受到限制，并且激活 FoxM1 可以绕过 β细胞增殖的固有制动。对于增殖刺激如何产生知之甚少 诱导Foxm1。我们的实验室发现结缔组织生长因子（CTGF）诱导 Foxm1 和成人 β 细胞在体内和离体小鼠胰岛以及人类体内的增殖 离体胰岛。 CTGF 具有这些作用的机制和信号通路 目前的影响尚不清楚这项研究利用独特的体内小鼠模型作为 以及对不同年龄的小鼠和人类胰岛的离体研究。在这个 建议我们将识别和操纵 β 细胞中的 CTGF 信号通路 增强成体β细胞增殖和再生的分子靶标。在 此外，我们还探讨了 FoxM1 激活增强 β 细胞的机制 增殖和存活，重点关注拮抗性前列腺素 E 受体 EP3 和 EP4，它们在胰岛中受到 FoxM1 的相互调节。我们假设 CTGF 通过整合素 β1 信号传导诱导 Foxm1 表达和成体 β 细胞 增殖，并且在 β 细胞死亡的情况下，CTGF 功能通过 巨噬细胞衍生的信号。我们进一步假设 FoxM1 激活克服了 与年龄相关的 β 细胞增殖变化部分是通过前列腺素的变化 受体活性。在本提案中，我们将： 1）确定信号传导途径 CTGF激活Foxm1表达和β细胞增殖； 2) 识别巨噬细胞- 与CTGF协同增强β细胞团再生的衍生因子；和 3) 确定前列腺素 EP 受体在 β 细胞增殖和存活中的作用。 这些研究旨在确定增强增殖和增殖的分子靶标。 老年 β 细胞的存活，目的是增加功能性 β 细胞量。