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: 7994334
• 负责人: DALE Leslie GREINER
• 金额: $ 208.94万
• 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/7994334
• 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）：Beta 细胞生物学联盟 (BCBC) 的使命是生成功能性人类葡萄糖反应性、产生胰岛素的 (-细胞)，并促进 (-细胞) 再生或现有 (-细胞) 的增殖。研究已经确定了许多转录因子和诱导信号促进小鼠胰岛发育的关键步骤，并且知识正在指导从干细胞和祖细胞生成人类β细胞的努力，我们还了解到小鼠和人类胰岛在以下方面存在显着差异：人类胰岛的细胞组成、功能、复制、再生能力和基因表达以及将啮齿动物胰岛生物学的新兴发现转化为人类胰岛的需要是我们基础广泛的跨学科科学团队的基础。由胰岛和干细胞生物学、胰岛再生、发育生物学和“人源化”小鼠方面的专家组成，将测试总体假设，即促进啮齿类动物（细胞增殖）的关键基因和/或环境刺激同样可以诱导增殖或人类的再生或非人类灵长类动物 (NHP)（-细胞。我们提出了三个具体目标：1）确定诱导小鼠（-细胞增殖）的信号是否也诱导人类和NHP（-细胞体内增殖）并评估局部炎症对人类和NHP（-细胞增殖）的影响。2）定义基因增殖的人类和 NHP (-细胞) 的表达谱，并基于这些发现诱导成人 (-细胞) 增殖。3) 识别和表征允许和限制啮齿动物、NHP 和人类出生后胰岛 (-细胞) 增殖的调节因子。重要的是，我们的研究团队将通过以下方式增强 BCBC 团队基于科学的努力：1) 专注于人类胰岛生物学，与从事小鼠胰腺和胰岛生物学和/或人类 ES 或 iPS 细胞研究的研究人员进行补充和协同；2) 增加大量的细胞；分子机制方面的专业知识（细胞发育、细胞命运决定和增殖；3）引入和开发有价值的研究工具和技术，例如“人源化”小鼠模型、体外和体内模型来研究增殖和增殖胎儿、青少年、成人和 NHP 胰岛的再生，以及独特的（细胞增殖和再生）小鼠模型。 公共卫生相关性：1 型和 2 型糖尿病中，产生胰岛素的细胞数量不足。这个跨学科团队正在致力于开发刺激人类胰岛素生成细胞增殖和再生的方法，作为糖尿病的新疗法。