Molecular Mechanisms of Human and Murine Beta Cell Proliferation and Regeneration

人类和小鼠β细胞增殖和再生的分子机制

• 批准号: 8316308
• 负责人: DALE Leslie GREINER
• 金额: $ 206.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316308
• 关键词: Adolescent; Adult; Beta Cell; Biology; Cell Proliferation; Cells; Cellular biology; Complement; Development; Developmental Biology; Gene Expression; Gene Expression Profile; Genes; Glucose; Human; In Vitro; Inflammation; Insulin; Islet Cell; Islets of Langerhans; Knowledge; Learning; Mission; Molecular; Mus; Natural regeneration; Pancreas; Proliferating; Research; Research Personnel; Rodent; Science; Signal Transduction; Stem cells; Stimulus; Technology; Testing; Translating; Work; base; diabetes mellitus therapy; endocrine pancreas development; fetal; in vivo; in vivo Model; induced pluripotent stem cell; islet; islet stem cells; mouse model; nonhuman primate; postnatal; public health relevance; regenerative; stem; stem cell biology; tool; transcription factor; type I and type II diabetes

DESCRIPTION (provided by applicant): The mission of the Beta Cell Biology Consortium (BCBC) is to generate functional human glucose-responsive, insulin-producing (-cells and to promote (-cell regeneration or proliferation of existing (-cells. While current research has identified many transcription factors and inductive signals that promote critical steps in mouse islet development, and that knowledge is guiding efforts to generate human beta cells from stem and progenitor cells, we have also learned that mouse and human islets differ significantly in terms of cellular composition, function, replication, regenerative capacity, and gene expression. These distinctive features of human islets and the need to translate emerging findings from rodent islet biology to human islets serve as the basis of our proposal. Our broad-based, interdisciplinary scientific team, consisting of experts in pancreatic islet and stem cell biology, islet regeneration, developmental biology, and "humanized" mice, will test the overall hypothesis that key genes and/or environmental stimuli which promote rodent (-cell proliferation can similarly induce the proliferation or regeneration of human or non-human primate (NHP) (-cells. We propose three specific aims: 1) Determine if signals that induce mouse (-cell proliferation also induce human and NHP (-cell proliferation in vivo and evaluate the effect of local inflammation on human and NHP (-cell proliferation. 2) Define the gene expression profile of proliferating human and NHP (-cells and build on these findings to induce proliferation of adult human (-cells. 3) Identify and characterize the regulators allowing and limiting postnatal islet (-cell proliferation in rodents, NHPs, and humans. Importantly, our investigative team will enhance the BCBC's team science-based efforts by: 1) focusing on human islet biology to complement and synergize with investigators working on either mouse pancreas and islet biology and/or human ES or iPS cells; 2) adding considerable expertise in the molecular mechanisms underlying (-cell development, cell fate determination, and proliferation; and 3) bringing and developing valuable research tools and technologies such as "humanized" mouse models, in vitro and in vivo models to study the proliferation and regeneration of fetal, juvenile, and adult human and NHP islets, and unique mouse models of (-cell proliferation and regeneration. PUBLIC HEALTH RELEVANCE: In both type 1 and type 2 diabetes, there are an insufficient number of insulin-producing cells. This interdisciplinary team is working to develop approaches to stimulate human insulin-producing cells to proliferate and regenerate as a new therapy for diabetes.

描述（由申请人提供）：β细胞生物学财团（BCBC）的使命是产生功能性的人类葡萄糖响应性，产生胰岛素的产生（ - 细胞和促进）（ - 细胞再生或增生（ - 重新再生或增殖）现有的现有研究（-Cells。当前的研究都在促进了许多转录因素，以促进了人类的发展，从而促进了人类的发展，并促进了Youse IS的发展。和祖细胞，我们还了解到，小鼠和人类的胰岛在细胞组成，功能，复制，再生能力和基因表达方面有显着差异。胰岛再生，发育生物学和“人性化”小鼠将检验总体假设，即促进啮齿动物的关键基因和/或环境刺激（-cell增殖可以同样诱导人或非人类灵长类动物（NHP）（-cells）的增殖或再生。我们提出了三个具体目的：1）确定是否诱导小鼠的信号（ - 细胞增殖也会诱导人和NHP（ - 体内 - 细胞增殖，并评估局部炎症对人和NHP的影响（-cell增殖。2）定义了人类和NHP的基因表达，并构建了人类和NHP的基因表达（-clive and thud）（-cells form of Human and Cells）（-Clive）（-Clive）（-clive and thud）（-cells of Human and copl）（-Clive offers and there）（-Clive）（-Cliveers fulls）（ - 构建）。表征允许和限制产后胰岛的调节器（ - 啮齿动物，NHP和人类的细胞增殖。基础（ - 细胞发育，细胞命运确定和增殖；以及3）带来和开发有价值的研究工具和技术，例如“人性化”小鼠模型，体外和体内模型，以研究胎儿，少年，成人人类和NHP小岛的增殖和再生，以及独特的小鼠模型（-cell of（-cell of）。 公共卫生相关性：在1型和2型糖尿病中，产生胰岛素的细胞数量不足。这个跨学科的团队正在努力开发方法，以刺激人类胰岛素的细胞，以增殖和再生为糖尿病的新疗法。