Genomic Basis for the Circadian Regulation of B-cell Function and Glucose Homeostasis

B 细胞功能和血糖稳态昼夜节律调节的基因组基础

基本信息

批准号：
9562882
负责人：
Benjamin John Weidemann
金额：
$ 5万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9562882
关键词：
ARNTL gene Acute Address Agonist Animals Appearance B-Lymphocytes Behavior Beta Cell Binding Binding Proteins Brain CRISPR/Cas technology Cell Line Cell Survival Cell physiology Cells ChIP-seq Chromatin Circadian Dysregulation Clinical Research Cues Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein DNA Data Development Diabetes Mellitus EP300 gene Enhancers Epidemic Exhibits Failure Feedback Functional disorder Genes Genetic Genetic Transcription Genetic study Genomics Glucose Histones Impairment Islets of Langerhans Knowledge Life Link Mediating Metabolic Diseases Metabolism Modeling Molecular Monitor Mus Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus NuRD complex Nutrient Pathogenesis Pathway interactions Pattern Periodicity Peripheral Physiological Physiology RNA Regulation Risk Factors Role Signal Transduction Sleep Sleep Wake Cycle Structure of beta Cell of islet System Testing Time Tissues Transcription Coactivator blood glucose regulation circadian circadian pacemaker circadian regulation combat epidemiology study exenatide gene repression glucagon-like peptide 1 glucose metabolism histone modification impaired glucose tolerance incretin hormone infancy insight insulin secretagogues insulin secretion islet molecular clock mutant recruit response shift work transcription factor transcriptome sequencing

项目摘要

Project Summary The circadian timing system is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolic processes with the sleep-wake cycle. Epidemiologic, clinical, and genetic studies indicate circadian disruption as an emerging risk factor in the development of diabetes. Our lab has demonstrated that genetic abrogation of the pancreatic β cell clock leads to acute hypoinsulinemic diabetes, and that insulin secretion exhibits basal and incretin-stimulated circadian regulation across the sleep- wake cycle. A remaining question is: How does the core circadian transcription mechanism modulate response to glucose and insulin secretagogues over the 24-hr timescale? Evidence from clock mutant pancreatic β-cells suggests that loss of clock activators produces impaired glucose-stimulated insulin secretion and broad changes in transcriptional activity at β-cell enhancers. These changes in transcription include pathways that intersect with those regulated by cAMP agonists, including the incretin hormones associated with meal-related insulin secretion. Indeed, islets stimulated with a glucagon-like peptide 1/cAMP agonist exhibited pronounced time-of-day dependent transcriptional and insulin secretion responses. The scientific premise of my present proposal is that the circadian clock controls time-of-day-dependent differences in the response to nutrient and meal-associated insulin secretagogues through the rhythmic regulation of β cell chromatin, in turn impacting glucose homeostasis throughout life. The studies in this proposal will provide new insight into the molecular pathophysiology underlying impaired glucose tolerance following circadian disruption in shiftwork and states of sleep perturbation.

项目摘要昼夜节律系统由Brain中存在的抗调节转录反馈编程与睡眠循环的代谢过程相协调的Ando周围组织。遗传研究表明昼夜节律的破坏是糖尿病发展的新兴危险因素。我们的实验室表明，胰腺β时钟的遗传废除导致急性低胰岛素糖尿病和胰岛素分泌在整个睡眠中表现唤醒周期。在24小时的时间尺度上对葡萄糖和胰岛素的泌尿蛋白的反应？胰腺β细胞表明，时钟激活剂的损失会导致葡萄糖诱导的胰岛素分泌受损 β细胞增强子的转录活性的广泛变化包括转录的变化与营地激动剂调节的途径相交，包括肠降凝素激素相关的途径确实，与饮食相关的绝缘分泌物。表现出明显的时间依赖性转录和胰岛素分泌反应我目前的提议的前提是，昼夜节律控制着日常的时间依赖于日期的差异通过β细胞的节奏调节对养分和餐食相关的胰岛素泌尿蛋白的反应染色质反过来影响葡萄糖稳态。深入了解昼夜节律后葡萄糖收缩受损受损的分子病理生理学在班次和睡眠扰动状态中。