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: 8717654
• 负责人: DALE Leslie GREINER
• 金额: $ 10万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717654
• 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.

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人类葡萄糖反应性、胰岛素产生性 (-细胞)，并促进 (-细胞) 再生或现有 (-细胞) 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，可促进小鼠胰岛发育的关键步骤，并且这些知识正在指导从干细胞产生人类 β 细胞的努力 和祖细胞，我们还了解到，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需要是我们提案的基础。我们基础广泛、跨学科的科学团队由胰岛和干细胞生物学专家组成， 胰岛再生、发育生物学和“人源化”小鼠将检验总体假设，即促进啮齿动物（-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灵长类（NHP）（-细胞）的增殖或再生。我们提出三个具体目标：1）确定诱导小鼠（-细胞）增殖的信号是否也诱导人类和 NHP （-体内细胞增殖，并评估局部炎症对人类和 NHP（-细胞增殖）的影响。2) 定义增殖的人类和 NHP（-细胞）的基因表达谱，并以这些发现为基础，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 NHP 出生后胰岛（-细胞）增殖的调节因子。 人类。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）在分子机制（细胞发育、细胞命运决定和增殖）方面增加大量专业知识；3）带来和开发有价值的研究工具和 诸如“人源化”小鼠模型、研究胎儿、青少年、成人和 NHP 胰岛增殖和再生的体外和体内模型，以及独特的细胞增殖和再生小鼠模型等技术。

项目成果

Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice.

• DOI: 10.1038/ncomms10991
• 发表时间: 2016-03-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Serr I;Fürst RW;Achenbach P;Scherm MG;Gökmen F;Haupt F;Sedlmeier EM;Knopff A;Shultz L;Willis RA;Ziegler AG;Daniel C
• 通讯作者: Daniel C

Loss of prohibitin induces mitochondrial damages altering β-cell function and survival and is responsible for gradual diabetes development.

• DOI: 10.2337/db13-0152
• 发表时间: 2013-10
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Supale S;Thorel F;Merkwirth C;Gjinovci A;Herrera PL;Scorrano L;Meda P;Langer T;Maechler P
• 通讯作者: Maechler P