"Expanding beta-cell mass"

“扩大β细胞量”

• 批准号: 8143503
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 130.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143503
• 关键词: Animal Model; Beta Cell; Cells; Cellular biology; Clinical; Collaborations; Development; Diabetes Mellitus; G Protein-Coupled Receptor Signaling; German population; Goals; Human; Immune response; Immune system; Immunology; Insulin; Knowledge; Life; Metabolism; Modeling; Monitor; Mus; Natural regeneration; Pancreas; Participant; Pathway interactions; Patients; Physiological; Play; Positioning Attribute; Pregnancy; Preparation; Production; Proteins; Research Personnel; Role; Science; Stress; Structure; Technology; Testing; Translating; Work; Zebrafish; embryonic stem cell; flexibility; human embryonic stem cell; in vivo; infancy; islet; pre-clinical; public health relevance; response; small molecule; stem cell biology; transdifferentiation

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.

描述（由申请人提供）：我们的总体目标是了解产生胰岛素的 β-细胞是如何产生的，并将该知识应用于为糖尿病患者生产 β-细胞。 我们在此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β细胞的发生和更新。我们将继续使用动物模型来确定β-细胞扩增技术如何在体内发挥作用——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且安全的人类疗法。 我们的具体目标探索 β 细胞发生的三种方法：新生、增殖和重编程/转分化： 具体目标 1：将再生筛选结果转化为人类 β 细胞。利用斑马鱼，我们发现了增强 β 细胞再生的小分子。我们将在人类胰岛和胚胎干细胞中验证这些作用，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 信号传导在 β 细胞发生中的功效。我们已经确定 GPCR 信号在 β 细胞扩增的两种生理环境中发挥着关键作用：妊娠和婴儿期。我们将测试这些途径在人类 β 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导致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编程中的作用，为将这些技术应用于人类治疗做好准备。 具体目标 4：监测和控制 β 细胞发生过程中的 ER 应激。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 应激和 UPR 在人类 ES 细胞和活小鼠的 β 细胞发生过程中的作用。 公共健康相关性：这些研究旨在将胰腺中产生胰岛素的细胞的产生机制的基础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。