Genetic control of mature beta cell function and identity

成熟 β 细胞功能和身份的遗传控制

基本信息

批准号：
10532236
负责人：
Barak Blum
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10532236
关键词：
Adult Affect Behavior Beta Cell Biological Process Cell Maturation Cell physiology Chronic stress Collaborations Consensus Coupled Data Set Development Diabetes Mellitus Disease Etiology Failure Functional disorder Gene Expression Genes Genetic Genetic Transcription Goals Growth Human In Vitro Insulin Resistance Insulin-Dependent Diabetes Mellitus Intervention Maps Metabolic stress Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Peripheral Phenotype Process Reporting Signal Pathway Stress System Testing autoimmune pathogenesis blood glucose regulation cell dedifferentiation diabetic diabetogenic environmental stressor functional restoration gene therapy in vivo insulin secretion islet mouse model novel pharmacologic postnatal development predictive modeling prevent stem cells transcriptome sequencing type I and type II diabetes

项目摘要

Project Summary/Abstract Functionally mature beta cells are essential to glucose homeostasis and their loss or dysfunction underlies all types of diabetes mellitus. In recent years, it has become clear that not all beta cells are permanently lost in either type of diabetes. Instead, chronically stressed beta cells lose their functionally mature phenotype and shift to a dysfunctional state in a process called de-differentiation. Preventing or reversing beta cell de- differentiation represents a promising approach to restoring functionally mature beta cell mass in diabetics. We have recently identified five novel genetic regulatory networks that we hypothesize to be important for regulat- ing mature beta cell function and identity. The overarching goal of this proposal is to establish the above five regulatory networks as novel genetic and pharmacological switches for controlling beta cell function and identi- ty. In Aim 1, we will map in detail each of the networks by determining direct and indirect regulated nodes for each regulator. We will further identify the networks' cellular function and find upstream signaling pathways predicted to affect the networks' behavior in both human and mouse beta cells, and their points of perturbation during beta cell de-differentiation. In Aim 2, we will test the causality of the five predicted regulators on beta cell function and identity in vitro in primary mouse and human islets, and in vivo, using genetic mouse models where available. We will further test the effect of genetic intervention points in the networks to lock in place ma- ture beta cell identity under the different diabetogenic stresses.

项目摘要/摘要功能上成熟的β细胞对于葡萄糖稳态至关重糖尿病类型。近年来，很明显，并非所有的beta细胞都永久丢失两种类型的糖尿病。相反，慢性应力的β细胞失去了功能成熟的表型和在称为脱不同的过程中转移到功能失调的状态。防止或逆转β细胞分化代表了一种在糖尿病患者中恢复功能成熟β细胞量的有前途的方法。我们最近已经确定了五个新型的遗传调节网络，我们假设对调节很重要成熟的β细胞功能和身份。该提议的总体目标是建立以上五个调节网络是用于控制β细胞功能和识别的新型遗传和药理开关泰。在AIM 1中，我们将通过确定直接和间接调节的节点的每个网络详细绘制每个调节器。我们将进一步识别网络的蜂窝函数并找到上游信号通路预计会影响人和小鼠β细胞中网络的行为及其扰动点在β细胞脱不同的过程中。在AIM 2中，我们将测试Beta细胞上五个预测调节剂的因果关系利用遗传小鼠模型的原代小鼠和人类胰岛中的功能和身份在哪里可用。我们将进一步测试网络中遗传干预点的效果，以锁定位置在不同的糖尿病性应力下进行β细胞的身份。