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Regulating stress response to promote postnatal beta-cell function and survival

调节应激反应以促进产后 β 细胞功能和存活

基本信息

批准号：
10199281
负责人：
Guoqiang Gu
金额：
$ 48.67万
依托单位：
VANDERBILT UNIVERSITY
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：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10199281
关键词：
5&apos Flanking Region ATF6 gene Acetylation Adult Affect Anabolism Attenuated B Cell Proliferation Beta Cell Cell Death Cell Line Cell Survival Cell Transplantation Cell physiology Cells Cessation of life ChIP-seq Complex Development Diabetes Mellitus Disease Down-Regulation Failure Family Financial compensation Functional disorder Gene Activation Gene Expression Genes Genetic Transcription Glucose Glucose Intolerance Goals Heat-Shock Response Histone Deacetylase Histone Deacetylation Histones Homeostasis Human Hyperglycemia Hypoglycemia Immunodeficient Mouse In Vitro Insulin Insulin Resistance Interruption Islet Cell Islets of Langerhans Knowledge Lead Link Mediating Messenger RNA Metabolic Metabolic stress Mitochondria Modeling Molecular Molecular Target Mus Myelin Non-Insulin-Dependent Diabetes Mellitus Obesity Open Reading Frames Output Oxidative Stress Peripheral Physiology Process Production Proinsulin Proteins Proteomics Publishing Reactive Oxygen Species Regulation Role Stress Structure of beta Cell of islet Testing Tissues Translations Up-Regulation Workload biological adaptation to stress blood glucose regulation gain of function gene product glucose metabolism improved in vivo in vivo evaluation insulin secretion islet islet stem cells knock-down novel paralogous gene postnatal prevent recruit response stressor transcription factor transcriptome sequencing

项目摘要

Workload-induced pancreatic islet β-cell dysfunction, loss-of identity, and cell death, commonly known as β-cell failure, is the hallmark of type 2 diabetes (T2D). This disease usually starts with obesity-induced insulin resistance, when peripheral tissues need higher levels of circulating insulin for glucose storage and usage. Islet β-cells compensate by expanding β-cell mass and increasing insulin output per cell, which requires upregulated insulin biosynthesis and oxidative glucose metabolism. These produce unfolded proinsulin in the ER and reactive oxygen species (ROS) in mitochondria, which at high levels can decimate β cells. Thus, β cells constantly activate stress response by stimulating the activity of several early-stage SRGs, including Atf6, IRE1, PERK, Hsf1, and Nurf2, to lead to: 1) attenuated overall protein translation; 2) enhanced translation of some SRG mRNAs that have special features such as upstream open reading frame (uORF) 5’ to the main ORF; 3) upregulated expression of some late-stage SRGs. The overall effect of these responses is to remove unfolded proteins/ROS for proteomic homeostasis and sustainable β-cell function. However, over-activating some late-stage SRGs such as Atf4 and Hsps induces β-cell failure by turning on some proapoptotic genes or by exceedingly lowering overall protein translation. Thus, it is imperative for β-cells to limit the levels of failure- causing SRGs for sustainable high-level of insulin output. An emerging model from our recent published findings is that a transcriptional complex containing Myt TFs and Sin3 can selectively repressing these failure- causing SRGs. Myt TFs are a family of three myelin transcription factors (Myt1, 2, and 3) highly expressed in islet cells. Sin3, including Sin3a and Sin3b, is a coregulator that represses transcription by recruiting histone deacetylases (HDACs) to modify histones. We showed that Myt TFs and Sin3 can form a transcription complex in β cells. Inactivating these genes in mouse and human β cells causes cell dysfunction and/or death while overactivating late-stage β-cell-failure-causing SRGs but not early stage SRGs. Intriguingly, Myt TFs, particularly Myt3, is induced by obesity-related stressors in mouse and human β cells, likely mediated by an uORF in 5’ flanking region of Myt3 mRNA. Importantly, MYT3 down-regulation accompanies human β-cell failure in T2D development. Our overarching hypothesis is that the stress-responsive Myt TFs, particularly Myt3, promote -cell function/survival by repressing late-stage SRGs via Sin3-mediated histone de-acetylation under both normal physiology and metabolic stress. Aim 1 will establish how MYT TFs repress SRG expression in a human β cell line and how manipulating MYT-TF levels will affect primary human β-cell function and survival. Aim 2 will define how metabolic stressors up-regulate Myt3 production and how this upregulation enable β-cell compensation under metabolic stress. We expect to uncover a tunable mechanism that can be explored for preventing/delaying β-cell failure and T2D.

工作负荷诱导的胰岛β细胞功能障碍，身份丧失和细胞死亡，通常被称为