"Expanding beta-cell mass"

描述(由申请人提供)：我们的总体目标是了解胰岛素产生的细胞是如何产生的，并将这一知识应用于糖尿病患者的细胞产生。 我们在这一应用中的一般方法是使用人类胰岛和人类胚胎干细胞来模拟人类？细胞的发生和翻转。我们将继续使用动物模型来确定细胞扩增技术在体内是如何工作的--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。 我们的具体目标是探索三种细胞发生的途径：新生、增殖和重新编程/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，我们已经确定了促进细胞再生的小分子。我们将在人类胰岛和ES细胞中验证这些攻击，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。 具体目的2：确定gpr信号在细胞发生中的作用。我们已经证实，GPCR信号在两种细胞扩增的生理环境中起着关键作用：妊娠和婴儿。我们将测试这些通路在人类细胞新生和更新中的重要性。 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造成胰腺损伤，并引发免疫反应。我们将确定这些反应在胰岛再生和重新编程中的作用，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过程中的内质网应激。我们已经开发了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内质网应激和UPR在人类ES细胞和活着的小鼠？细胞发生过程中的作用。 公共卫生相关性：这些研究旨在将胰腺中产生胰岛素的细胞产生机制的基本知识应用于临床问题，即如何为糖尿病患者产生更多的胰岛素产生细胞。

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.