Modulating intrinsic beta cell stress to block diabetes pathogenesis

调节内在 β 细胞应激以阻止糖尿病发病机制

基本信息

批准号：
10647729
负责人：
Matthias Hebrok
金额：
$ 66.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647729
关键词：
Address Affect Alleles Beta Cell Blood Glucose Cell Nucleus Cell physiology Cells Cellular Stress Chemistry Clustered Regularly Interspaced Short Palindromic Repeats Cytoprotection Cytosol Data Defect Degenerative Disorder Deterioration Diabetes Mellitus Disease Disease Progression Endoplasmic Reticulum Functional disorder Genetic Genetic Transcription Goals Health Hormone secretion Human Human Engineering Insulin Intervention Islet Cell Maintenance Marriage Mitochondria Modeling Molecular Organelles Outcome Output Pancreas Participant Pathology Pathway interactions Pharmacology Physiological Population Prevention Production Productivity Protein Biosynthesis Proteins Role Secretory Cell Severity of illness Signal Pathway Signal Transduction Stress System Testing Therapeutic Therapeutic Intervention Variant Work biological adaptation to stress cell dedifferentiation chemical genetics coping mechanism diabetes pathogenesis dimer endoplasmic reticulum stress engineered beta cell exhaustion human embryonic stem cell human stem cells innovation insight insulin secretion kinase inhibitor loss of function novel novel strategies novel therapeutics pharmacologic preservation prevent progenitor protein folding response sensor small molecule stem stem cell population stem cells therapy design tool transcription factor type I and type II diabetes

项目摘要

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.

项目摘要/摘要糖尿病及其并发症会影响全球人口中不断增长的部分。最近的研究指出 β细胞缺陷是1型和2型糖尿病中的共同点。在这里，我们建议讯问 β细胞中存在的不同应对机制的贡献，可防止生理压力，但其功能障碍会导致β细胞在扩展或未解决的压力。我们专注于ER应力之间的连接，从而导致展开蛋白质反应（UPR）和由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的相互作用以及它们如何告知β细胞功能。拟议的工作仅在人类β细胞中进行，并利用我们产生和CRISPR的能力修饰人类干细胞群体产生细胞的功能性胰岛素。我们提议的总体目标研究是为了定义导致β细胞功能障碍和随后的糖尿病的机制，清晰专注于确定可以利用治疗干预的信号节点。我们有组建了一支有关这些特定蜂窝结果的领先专家团队，并开发了药理以及解决β细胞中停止压力反应的遗传工具如何改变疾病的进程。我们姿势认为直接靶向β细胞中的应力反应途径是一种创新的新方法糖尿病治疗和预防也对其他退化性疾病具有影响。