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: 8142740
• 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/8142740
• 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)的使命是产生功能性的人类葡萄糖反应、胰岛素产生(-细胞)，并促进(-细胞)再生或现有(-细胞)的增殖。虽然目前的研究已经确定了许多转录因子和诱导信号，这些转录因子和诱导信号促进了小鼠胰岛发育的关键步骤，而且这些知识正在指导从干细胞和祖细胞生成人类β细胞的努力，但我们也了解到，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存在显著差异。人类胰岛的这些独特特征，以及将啮齿动物胰岛生物学的新发现转化为人类胰岛的需要，是我们提案的基础。我们基础广泛的跨学科科学团队，由胰岛和干细胞生物学、胰岛再生、发育生物学和“人性化”小鼠的专家组成，将测试促进啮齿动物(-细胞)增殖的关键基因和/或环境刺激可以类似地诱导人类或非人灵长类(NHP)(-细胞)增殖或再生的总体假设。我们提出了三个具体目标：1)确定诱导小鼠(-细胞)增殖的信号是否也在体内诱导人和NHP(-细胞)增殖，并评估局部炎症对人和NHP(-细胞)增殖的影响。2)确定增殖期人类和NHP(-)细胞的基因表达谱，并在此基础上诱导成人(-)细胞的增殖。3)确定和描述允许和限制鼠类、NHP和人类的出生后胰岛(-细胞)增殖的调节因素。重要的是，我们的调查团队将通过以下方式加强BCBC团队以科学为基础的努力：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细胞的研究人员相互补充和协同；2)在(-细胞发育、细胞命运决定和增殖)潜在的分子机制方面增加相当多的专业知识；以及3)带来和开发有价值的研究工具和技术，如“人性化”小鼠模型，体外和体内模型，以研究胎儿、青少年和成年人类和NHP胰岛的增殖和再生，以及独特的(-细胞)增殖和再生的小鼠模型。 公共卫生相关性：在1型和2型糖尿病中，胰岛素产生细胞的数量都不足。这个跨学科的团队正在努力开发刺激人类胰岛素产生细胞增殖和再生的方法，作为糖尿病的一种新疗法。