Modulating intrinsic beta cell stress to block diabetes pathogenesis

项目总结/摘要 糖尿病及其并发症影响着全球越来越多的人口。最近的研究表明， 2型糖尿病的发病机制有哪些？在这里，我们建议审问 β细胞中存在的不同应对机制的贡献， 压力，但其功能障碍可导致β细胞在 长期或未解决的压力。我们专注于ER应力导致的展开之间的联系 蛋白质反应（UPR）和β细胞身份的新调节剂引起的β细胞身份的丧失。我们 建议确定这些途径如何相互作用以及它们如何告知β细胞功能。拟议工作 是专门在人类β细胞中进行，并利用我们的能力，产生和CRISPR- 从人类干细胞群体中修饰功能性胰岛素产生细胞。我们提出的总体目标是 研究的目的是确定导致β细胞功能障碍和随后的糖尿病的机制， 重点是识别那些可以用于治疗干预的信号节点。我们有 组建了一个领先的专家团队，研究这些特定的细胞结果，并开发了药理学 以及基因工具来解决β细胞中停止应激反应如何改变疾病的进程。我们 我认为直接靶向β细胞中的应激反应途径是一种创新和新颖的方法， 糖尿病的治疗和预防也对其他退行性疾病有影响。

Project Summary/Abstract Diabetes and its complications affect an ever-growing part of the global population. Recent studies point to beta cell defects as a common denominator in Type 1 and Type 2 diabetes. Here, we propose to interrogate the contribution of distinct coping mechanisms present in beta cells that serve to protect against physiological stress, but whose dysfunction can result in deterioration or destruction of beta cells under conditions of extended or unresolved stress. We focus on the connections between ER stress resulting in the unfolded protein response (UPR) and loss of beta cell identity caused by a novel regulator of beta cell identity. We propose to determine how these pathways interact and how they inform beta cell function. The proposed work is exclusively performed in human beta cells and takes advantage of our ability to generate and CRISPR- modify functional insulin producing cells from human stem cell populations. The overall goal of our proposed studies is to define the mechanisms resulting in beta cell dysfunction and subsequent diabetes, with a clear focus on identifying those signaling nodes that can be exploited for therapeutic intervention. We have assembled a team of leading experts on these specific cellular outcomes and have developed pharmacological and genetic tools to address how halting stress response in beta cells can alter the course of the disease. We pose that directly targeting stress response pathways in beta cells is an innovative and novel approach to diabetes treatment and prevention that also has implications for other degenerative diseases.