Molecular Mechanisms of Human and Murine Beta Cell Proliferation and Regeneration

描述（由申请人提供）：β细胞生物学联盟（BCBC）的使命是生成功能性的人葡萄糖反应性、胰岛素生成细胞，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促进小鼠胰岛发育关键步骤的转录因子和诱导信号，并且这些知识正在指导从干细胞和祖细胞中产生人类β细胞的努力，但我们也了解到小鼠和人类胰岛在细胞组成，功能，复制，再生能力和基因表达方面存在显着差异。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必要性是我们建议的基础。我们的基础广泛，跨学科的科学团队，由胰岛和干细胞生物学，胰岛再生，发育生物学和“人源化”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/或环境刺激同样可以诱导人类或非人类灵长类（NHP）细胞的增殖或再生的整体假设。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诱导体内人和NHP细胞增殖，并评估局部炎症对人和NHP细胞增殖的影响。2)定义增殖的人和NHP细胞的基因表达谱，并在这些发现的基础上诱导成人细胞的增殖。3)鉴定和表征啮齿类动物、NHPs和人类允许和限制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加强BCBC团队基于科学的工作：1)专注于人类胰岛生物学，以补充和协同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；2)在细胞发育、细胞命运决定和增殖的分子机制方面增加相当多的专业知识；3)带来和开发有价值的研究工具和技术，如“人源化”小鼠模型，体外和体内模型，研究胎儿、少年、成人和NHP胰岛的增殖和再生，以及独特的小鼠细胞增殖和再生模型。

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.