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Uncovering Two Novel Diabetes Drug Targets in the IDG

IDG 发现两种新型糖尿病药物靶点

基本信息

批准号：
9813755
负责人：
Gregory Michael Ku
金额：
$ 16.07万
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：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813755
关键词：
Adhesions Alleles Beta Cell Biological Assay Cell Death Cell Line Cell Survival Cell physiology Cells Chloride Channels Collection Coupling Data Defect Development Diabetes Mellitus Disease Disease Progression Dose Dreams Drug Targeting Endoplasmic Reticulum Environment Future G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Generations Genes Genome Glucose Glucose Intolerance Glucose tolerance test Goals Grant Heat shock proteins Hyperglycemia Hypoglycemia Individual Insulin Insulin Resistance Knock-out Knockout Mice Ligands Link Long-Acting Insulin Measurement Measures Mus Mutation Neurons Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Pharmaceutical Preparations Phenotype Physiological Plasma Play Production Proteins Pulmonary Surfactants RNA interference screen Resources Retina Role Signal Transduction Stress Structure of beta Cell of islet Testing Therapeutic Therapeutic Intervention Tissues base blood glucose regulation digital effective therapy endoplasmic reticulum stress genome wide association study high throughput screening improved in vivo insulin secretion islet knockout gene mouse model new therapeutic target novel novel therapeutics pandemic disease phenotypic data response surfactant production targeted treatment whole genome

项目摘要

Project Summary/Abstract Nearly 10% of the world has diabetes and this number is projected to increase. Type 2 diabetes occurs when beta cells fail to produce sufficient insulin in the face of insulin resistance. Current therapies are inadequate and many patients eventually become insulin dependent. Though we now have many forms of short and long acting insulins, insulin still has a small therapeutic window with a high chance of hyperglycemia and hypoglycemia with just slight errors in dosing. Therefore, new therapies are needed. Our long term goal is to find new therapeutic targets in the pancreatic beta cell to improve overall function and survival. In this R03, we propose to study beta-cell specific knockout mice of the two IDG-eligible genes. One is an endoplasmic reticulum (ER) resident protein that has been linked to ER stress. The second is a GPCR. Notably, both ER stress and GPCRs have been fertile grounds for development of diabetes drugs so these studies could have future therapeutic relevance. We hypothesize that loss of the ER protein will trigger ER stress in the pancreatic beta cell, resulting in beta cell death, while loss of the GPCR in beta cells will result in defective glucose stimulated insulin secretion (GSIS) due to reduced Gq signaling. Aim 1: Characterize the glucose homeostasis of a beta cell-specific knockout mouse of this ER resident protein with a focus on the unfolded protein response. Because of a potential role in ER stress in other tissues, we hypothesize that loss of this gene in the beta cell will result in ER stress and beta cell death, resulting in diabetes. We will perform glucose tolerance testing of these mice with concomitant measurement of basal and stimulated plasma insulin levels. We will study insulin secretion by islet perifusion. We will measure beta cell mass using a novel digital PCR assay and beta cell death using immunostaining. Finally, we will measure markers of the unfolded protein response. Aim 2: Characterize the glucose homeostasis of a beta cell-specific GPCR knockout mouse with a focus on insulin secretion. Given the Gq coupling of this GPCR and the known role of Gq in insulin secretion, we hypothesize the major defect in these beta cell specific knockouts will be in insulin secretion. We will also ask if a natural ligand of this GPCR, which appears to be normally expressed in the islet, can stimulate insulin secretion. The expected outcomes of this R03 proposal will be the identification of two new targets for diabetes therapeutics aimed at improving pancreatic beta cell function. This grant will also allow us to develop a pipeline to study additional IDG genes in vivo in the beta cell as the collection of IDG knockout mice expands.

项目总结/文摘