Biology of nuclear receptor Rev-erb alpha in circadian rhythm and metabolism

核受体 Rev-erb α 在昼夜节律和代谢中的生物学

基本信息

批准号：
8136072
负责人：
Lei Yin
金额：
$ 24.64万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-23 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136072
关键词：
A Mouse Adaptor Signaling Protein Address Adenoviruses Animal Model Animals Applications Grants Behavior Biology Cell Culture Techniques Cell Line Cells Circadian Rhythms Clock protein Commit Complex Core Facility Country Cues Data Degenerative Disorder Development Diabetes Mellitus Disease Drug Delivery Systems Electronic Mail Embryo Energy Metabolism Environment Epidemic Figs - dietary Future Gel Gene Expression Genes Gluconeogenesis Goals Grant Health Hepatocyte Homeostasis Human In Vitro Individual Injection of therapeutic agent Institution Insulin Resistance Knock-out Knowledge Laboratories Laboratory Animal Medicine Lead Light Link Liver Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediating Messenger RNA Metabolic Metabolic Diseases Metabolic Pathway Metabolism Methods Michigan Molecular Morbidity - disease rate Mus Nuclear Orphan Receptor Nuclear Receptors Obesity Pathogenesis Pathway interactions Pennsylvania Persons Phase Phenotype Phosphorylation Physiological Physiology Play Preparation Process Proteins Proteomics Protocols documentation Publications Recombinants Recruitment Activity Regulation Research Research Personnel Research Proposals Role Sampling Serum Services Shock Signal Transduction Site Study models Supervision System Tail Training Transgenic Animals Translating Ubiquitination United States Universities Update Variant Veins Viral Virus Work Yin animal care base career circadian pacemaker cryptochrome 1 cullin 4A fasting glucose glucose metabolism glucose tolerance hepatoma cell high risk improved in vivo insight insulin sensitivity insulin signaling interest medical schools mouse model multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutic intervention overexpression relating to nervous system transgene expression treatment strategy ubiquitin-protein ligase vector

项目摘要

Obesity and diabetes have reached epidemic level in the United States. Diabetes and its associated complications are becoming one of the leading causes of morbidity In this country. Although several hypotheses link obesity and Insulin resistance, the role of circadian rhythm in the pathogenesis of diabetes has not been well addressed. Interestingly, there Is a clear circadlan variation In fasting glucose, Insulin sensitivity and glucose tolerance, which Is severely dampened In the condition of obesity and diabetes. The orphan nuclear receptor Rev-erba emerged as a core circadian gene. By repressing gene expression of another clock gene Bmal1, Rev-erba functions as a negative regulator of circadian rhythm. We showed GSK3p-dependent phosphorylation is required for maintaining the protein stability of Rev-erba and is crucial for synchronizing the circadlan oscillation of Email gene In vitro. To extend our knowledge on GSK3pdependent regulation of Rev-erba, we propose two specific aims in the first phase of this application (K99 phase), including: aim 1. Elucidate the signal patliways upstream of GSKSp mediating Rev-erba degradation in hepatocytes; aim 2. Determine in vivo roles of Rev-erba phosphorylation by GSKSp in circadian rhythm and metabolism. A mouse model expressing Rev-erba mutant which mimics GSK3P phosphorylation In liver will be created to address these questions. This will be the first analysis to detemnine the role of Rev-erba as a clock protein In liver circadlan rhythm and glucose metabolism. This study will be carried out in the Penn Diabetes Center at University of Pennsylvania under the supervision of Dr. Mitchell Lazar. The center has expertise in diabetes and obesity research, and will provide outstanding environment to conduct the proposed project. Meanwhile, the project will provide superb training for the principle Investigator, Dr. Lel Yin, to develop academic career In the field of diabetes and obesity. The role of the ubiquitln-proteasome pathway (UPP) has not been well-studied In the process of metabolism and energy homeostasis. We recently discovered that Cullln 4A-based E3 ligase regulates protein stability of Rev-erba as well as gene expression Important for gluconeogenesis, suggesting Cullln 4A is a novel modulator functioning in both circadlan rhythm and metabolism. Therefore, the specific aim 3 proposed during the ROO phase will be focused on unraveling roles of the Cullin 4A E3 ubiquitin ligase in regulating circadian rhythm, insulin signaling and glucose metabolism. We expect this work will provide a panel of evidences for the functional Importance of the ubiqultin-proteaspme system in the regulation of metabolism. In addition, this work may shed the new light on Identifying the new therapeutic targets for treating Insulin resistance and diabetes.

在美国，肥胖和糖尿病已经达到流行水平。糖尿病及其相关的并发症已成为该国发病率的主要原因之一。虽然有几个假设连接肥胖和胰岛素抵抗，昼夜节律在糖尿病发病机理中的作用尚未得到很好的解决。有趣的是，空腹葡萄糖，胰岛素敏感性和葡萄糖耐受性存在明显的圆形变化，在肥胖和糖尿病的状态下严重抑制了葡萄糖耐受性。孤儿核受体Rev-Erba成为核心昼夜节律基因。通过抑制另一个时钟基因BMAL1的基因表达，Rev-erba起着昼夜节律的负调节剂。我们表明需要GSK3P依赖性磷酸化对于维持Rev-Erba的蛋白质稳定性需要，并且对于在体外同步电子邮件基因的Circadlan振荡至关重要。为了扩展我们对Rev-Erba的GSK3PDDENS的了解，我们在本应用的第一阶段（K99阶段）提出了两个具体目标，包括：AIM 1。阐明GSKSP上游介导Rev-Erba降解肝细胞中的Rev-Erba降解的信号； AIM 2。确定GSKSP在昼夜节律和代谢中的Rev-Erba磷酸化的体内作用。将创建一种表达Rev-Erba突变体的小鼠模型，该模拟肝脏中的GSK3P磷酸化将创建以解决这些问题。这将是第一次判断Rev-Erba作为时钟蛋白在肝Circadlan节奏和葡萄糖代谢中的作用的分析。这项研究将在米切尔·拉扎尔（Mitchell Lazar）博士的监督下在宾夕法尼亚大学的宾夕法尼亚大学糖尿病中心进行。该中心在糖尿病和肥胖研究方面具有专业知识，并将为进行拟议项目提供杰出的环境。同时，该项目将为主要调查员Lel Yin博士提供出色的培训，以发展糖尿病和肥胖领域的学术生涯。在泛素化途径（UPP）的作用中，在此过程中尚未得到充分研究代谢和能量稳态。我们最近发现，基于CULLLN 4A的E3连接酶调节Rev-Erba的蛋白质稳定性以及对糖异生很重要的基因表达，这表明CULLLN 4A是一种在Circadlan节奏和代谢中的新型调节剂。因此，在ROO阶段提出的特定目的3将集中在揭示Cullin 4A E3泛素连接酶在调节昼夜节律，胰岛素信号传导和葡萄糖代谢中的作用。我们预计这项工作将为Ubiqultin-Proteaspme系统在代谢调节中的功能重要性提供一组证据。此外，这项工作可能会为识别用于治疗胰岛素耐药性和糖尿病的新治疗靶点的新灯光。