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.

项目总结/摘要 2型糖尿病（T2 D）不成比例地影响退伍军人群体：而9% 美国总人口的10%患有T2 D，25%的退伍军人患有T2 D。 这种疾病。成人β细胞群通常通过复制响应胰岛素而增加 抵抗，但β细胞增殖失败加上β细胞死亡增加导致T2 D。T2d 发病率随着年龄的增长而增加，部分原因是β细胞对 随着年龄的增长，我们的实验室将FoxM 1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 对几种β细胞增殖刺激的反应。胰岛中Foxm 1的表达随着 在小鼠和人类中，FoxM 1在老年小鼠β细胞中的激活增加了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FoxM 1在老年β细胞中是有限的，激活FoxM 1可以绕过 β细胞增殖的内在制动。关于增殖性刺激物 诱导Foxm 1。我们的实验室发现结缔组织生长因子（CTGF）诱导 Foxm 1与小鼠体内、离体和人胰岛中的成体β细胞增殖 离体胰岛。CTGF具有这些功能的机制和信号通路 该研究利用独特的体内小鼠模型， 以及来自不同年龄的小鼠和人胰岛的离体研究。在这 我们将鉴定和操纵β细胞中的CTGF信号通路， 用于增强成体β细胞增殖和再生的分子靶点。在 此外，我们还探讨了FoxM 1激活增强β细胞增殖的机制， 增殖和存活，侧重于拮抗性前列腺素E受体EP 3 和EP 4，它们在胰岛中受FoxM 1的间接调节。我们假设 CTGF通过整合素β1信号转导诱导Foxm 1表达和成体β细胞 在β细胞死亡的情况下，CTGF的功能被增强， 巨噬细胞衍生的信号。我们进一步假设FoxM 1激活克服了 β细胞增殖的年龄相关变化部分通过前列腺素的改变 受体活性在这项提案中，我们将：1）确定信号通路， CTGF激活Foxm 1表达和β细胞增殖; 2）鉴定巨噬细胞- 与CTGF协同作用以增强β细胞团再生的衍生因子;以及3） 确定前列腺素EP受体在β细胞增殖和存活中的作用。 这些研究旨在确定分子靶点，以增强增殖， 目的是增加功能性β细胞群。