Modulating intrinsic beta cell stress to block diabetes pathogenesis

项目摘要/摘要 糖尿病及其并发症影响着全球人口中越来越多的人。最近的研究指出 β细胞缺陷是1型和2型糖尿病的共同特征。在这里，我们建议审问 在贝塔细胞中存在的不同应对机制的作用，这些机制有助于防止生理性的 应激，但其功能障碍可导致在以下条件下β细胞的退化或破坏 延长的或未解决的压力。我们着重于内质网应激导致的展开之间的联系 蛋白质反应(UPR)和β细胞特性的丧失由一种新的β细胞特性调节器引起。我们 建议确定这些通路是如何相互作用的，以及它们是如何影响β细胞功能的。拟议中的工作 专门在人类β细胞中执行，并利用我们产生和CRISPR的能力- 从人类干细胞群体中修饰产生胰岛素的功能性细胞。我们建议的总体目标是 研究是为了确定导致β细胞功能障碍和随后的糖尿病的机制，并明确 重点识别那些可用于治疗干预的信号节点。我们有 组建了一个关于这些特定细胞结果的领先专家团队，并开发出了药理学 以及基因工具，以解决停止β细胞的应激反应如何改变疾病的过程。我们 提出直接针对β细胞中的应激反应通路是一种创新和新颖的方法 糖尿病的治疗和预防对其他退行性疾病也有影响。

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.