"Expanding beta-cell mass"

描述（由申请人提供）：我们的总体目标是了解如何产生胰岛素？细胞产生，并将这些知识应用于生产？为糖尿病患者提供细胞。 我们在此应用中的一般方法是使用人胰岛和人胚胎干细胞来模拟人？细胞生成和转化。我们将继续使用动物模型来确定如何？细胞扩增技术在体内起作用--它们如何与免疫系统相互作用并影响新陈代谢--以便将这些想法发展成实用和安全的人类疗法。 我们的具体目标探索了三种方法，细胞发生：新生、增殖和重编程/转分化： 具体目标1：将再生筛选的结果转化为人类？细胞利用斑马鱼，我们已经确定了小分子，增强？细胞再生我们将在人类胰岛和ES细胞中验证这些命中，探索它们的作用机制，并在临床前动物模型中测试它们的活性。 具体目标2：确定GPCR信号转导在？细胞发生我们已经确定，GPCR信号在两种生理环境中起着关键作用？细胞扩增：怀孕和婴儿期。我们将测试这些途径的重要性，在新生和营业额的人？细胞 具体目标3：确定免疫系统在胰岛再生中的作用。目前的胰岛再生模型都会引起胰腺损伤并引起免疫反应。我们将确定这些反应在胰岛再生和重编程中的作用，为将这些技术应用于人类治疗做准备。 具体目标4：监测和控制？-细胞发生我们开发了用于监测和控制活细胞中未折叠蛋白反应（UPR）的技术。我们将利用这些技术来确定ER应力和UPR在？在人ES细胞和活小鼠中的细胞发生。 公共卫生相关性：这些研究旨在将胰腺中产生胰岛素细胞的机制的基本知识应用于如何为糖尿病患者产生更多这些细胞的临床问题。

DESCRIPTION (provided by applicant): Our overall goal is to understand how insulin-producing ?-cells are generated and to apply that knowledge to the production of ?-cells for patients with Diabetes. Our general approach in this application is to use human islets and human embryonic stem cells to model human ?-cell genesis and turn over. We will continue to use animal models to determine how ?-cell expansion technologies work in vivo -- how they interact with the immune system and impact metabolism -- in order to develop these ideas into practical and safe human therapies. Our Specific Aims explore three approaches to ?-cell genesis: neogenesis, proliferation, and reprogramming/transdifferentiation: Specific Aim 1: Translate results of regeneration screens to human ?-cells. Using zebrafish, we have identified small molecules that enhance ?-cell regeneration. We will validate these hits in human Islets and ES cells, explore their mechanisms of action, and test their activity in preclinical animal models. Specific Aim 2: Determine the efficacy of GPCR signaling in ?-cell genesis. We have established that GPCR signaling plays a critical role in two physiologic settings of ?-cell expansion: pregnancy and infancy. We will test the importance of these pathways in the neogenesis and turnover of human ?-cells. Specific Aim 3: Establish the role of the immune system in islet regeneration. Current models of islet regeneration all cause pancreatic damage and provoke an immune response. We will determine the role of these responses in islet regeneration and reprogramming in preparation for moving these technologies to human therapy. Specific Aim 4: Monitor and control ER stress during ?-cell genesis. We have developed technologies for monitoring and controlling the unfolded protein response (UPR) in living cells. We will utilize these technologies to determine the role of ER stress and the UPR during ?-cell genesis in human ES cells and live mice. PUBLIC HEALTH RELEVANCE: These studies are directed towards the application of basic knowledge of the mechanisms by which the insulin producing cells in the pancreas are generated to the clinical problem of how to produce more of these cells for patients with Diabetes.