Genetic control of mature beta cell function and identity

成熟 β 细胞功能和身份的遗传控制

• 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
• 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

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.

项目总结/摘要 功能成熟的β细胞对葡萄糖稳态是必不可少的，它们的丧失或功能障碍是所有 糖尿病的类型近年来，已经清楚的是，并非所有的β细胞都永久性地丢失， 任何一种类型的糖尿病。相反，长期应激的β细胞失去其功能成熟的表型， 在一个被称为去分化的过程中转变为功能失调的状态。预防或逆转β细胞脱- 分化代表了恢复糖尿病患者中功能成熟β细胞群的有希望的方法。我们 最近发现了五种新的基因调控网络，我们假设它们对调节 成熟的β细胞功能和身份。本提案的总体目标是建立上述五个 调节网络作为控制β细胞功能和识别的新型遗传和药理学开关， 泰在目标1中，我们将通过确定直接和间接调节节点来详细映射每个网络， 每个调节器。我们将进一步确定网络的细胞功能，并找到上游信号通路 预测会影响人类和小鼠β细胞中网络的行为，以及它们的扰动点 在β细胞去分化过程中。在目标2中，我们将测试五个预测的调节因子对β细胞的因果关系。 在原代小鼠和人胰岛中的体外功能和特性，以及使用遗传小鼠模型的体内功能和特性 在可用的地方。我们将进一步测试网络中基因干预点的效果，以锁定在适当的位置， 不同致糖尿病应激下的真实β细胞身份。