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Creating a mouse and human model of a novel monogenic diabetes syndrome

创建新型单基因糖尿病综合征的小鼠和人类模型

基本信息

批准号：
10452292
负责人：
Gregory Michael Ku
金额：
$ 16.15万
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：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452292
关键词：
2019-nCoV Amino Acid Substitution Amino Acids Aspartate Backcrossings Beta Cell Biosensor Blindness COVID-19 CRISPR/Cas technology Calcium Cell Death Cell Survival Cell model Cell physiology Cell secretion Cells Chloride Channels Chlorides Data Databases Development Diabetes Mellitus Disease model Endoplasmic Reticulum Funding Future Genes Genome Glucose Glutamates Grant Health Care Costs Health Expenditures Human Impairment In Vitro Individual Insulin Insulin Resistance Knockout Mice Maintenance Measures Membrane Modeling Movement Mus Mutation Neurons Non-Insulin-Dependent Diabetes Mellitus Organelles Patients Penetrance Persons Phenotype Play Point Mutation Positioning Attribute Process Proteins Retina Retinitis Pigmentosa Role Structure of beta Cell of islet Syndrome Testing Tissues United States National Institutes of Health blood glucose regulation diabetes risk disease-causing mutation druggable target effective therapy endoplasmic reticulum stress high risk human disease human model human pluripotent stem cell improved in vivo insulin secretion mRNA Expression mouse model new therapeutic target novel novel therapeutics response screening therapeutic target transcriptome sequencing

项目摘要

Project Summary/Abstract One in eleven people has diabetes mellitus worldwide. Despite the development of novel therapeutics in the last decade, type 2 diabetes is progressive in most patients, showing that more effective therapies are needed. Our long-term objective is to identify genes that are important for beta cell function because these may reveal causes and therapeutic targets for diabetes. We identified a chloride channel as a potential regulator of glucose homeostasis. This channel is known to play a role in maintaining normal levels endoplasmic reticulum (ER) stress, a key process for pancreatic beta cell function and survival. A single amino acid substitution in this channel has been associated with early blindness in humans. The central focus of this grant is to model this mutation in mice and in human pluripotent stem cells to understand if and how this mutation leads to diabetes. Our central hypotheses are that this channel is required for maintenance of pancreatic beta cell ER stress and that the point mutation will result in pancreatic beta cell death from ER stress and diabetes in both mice and humans. Aim 1: Model this chloride channel mutation in mice. Mice homozygous for the mutation will be tested for diabetes. Isolated beta cells will be tested for the levels of ER chloride and the expression of markers of the unfolded protein response (UPR). We hypothesize that homozygous mice will develop diabetes, their beta cells will have lower levels of ER chloride, and markers of UPR will be upregulated. Aim 2: Create a human beta cell model of the mutation. As useful as mouse models of human disease can be, human beta cells are not exactly the same as mouse beta cells. Therefore, in this aim, we will introduce the homozygous mutation into human pluripotent stem cells and assess the ability of these cells to differentiate into enriched beta cell clusters (eBCs) in vitro. We will then assess ER stress and insulin secretion from these cells. We hypothesize that the mutation will cause decreased ER chloride, ER stress, and impaired insulin secretion. This grant will elucidate a novel role for a chloride channel in beta cell function. These studies will be significant because they may identify a novel monogenic cause of human diabetes and elucidate a novel requirement of ER chloride transport in the maintenance of ER stress.

项目总结/文摘