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

• 批准号: 7936289
• 负责人: Lei Yin
• 金额: $ 24.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/7936289
• 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

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.

肥胖症和糖尿病在美国已经达到流行水平。糖尿病及其相关疾病 并发症正在成为这个国家发病率的主要原因之一。尽管有几个 假设肥胖和胰岛素抵抗有关，但昼夜节律在糖尿病发病机制中的作用还没有得到很好的解决。有趣的是，空腹血糖、胰岛素敏感性和糖耐量存在明显的周围性变化，在肥胖和糖尿病的情况下，这种变化会严重减弱。 孤儿核受体rev-erba是一个核心的昼夜节律基因。通过抑制另一个时钟基因BMal1的基因表达，REV-ERBA作为昼夜节律的负调节因子发挥作用。我们的研究表明，依赖于GSK3p的磷酸化是维持Rev-erba蛋白稳定性所必需的，也是体外同步电子邮件基因Circadlan振荡的关键。为了扩大我们对Rev-erba依赖于GSK3p的调控的认识，我们在应用的第一阶段(K99阶段)提出了两个特定的目标，包括：目的1.阐明GSKSp上游的信号通路介导肝细胞中Rev-erba的降解；目的2.在体内确定GSKSp对Rev-erba的磷酸化在昼夜节律和代谢中的作用。为了解决这些问题，将建立一个表达REV-ERBA突变体的小鼠模型，该突变体模拟肝脏中GSK3P的磷酸化。这将是确定Rev-erba作为时钟蛋白在肝脏昼夜节律和葡萄糖代谢中的作用的第一次分析。这项研究将在宾夕法尼亚大学的宾夕法尼亚糖尿病中心进行，由米切尔·拉扎尔博士监督。该中心在糖尿病和肥胖症研究方面拥有专业知识，并将为实施拟议的项目提供出色的环境。同时，该项目将为首席研究员尹乐民博士提供卓越的培训，以发展糖尿病和肥胖症领域的学术生涯。 泛素-蛋白酶体途径(Upp)在肿瘤发生、发展过程中的作用尚未得到很好的研究。 新陈代谢和能量动态平衡。我们最近发现了基于cullln 4A的E3连接酶调节Rev-erba的蛋白质稳定性以及糖异生的重要基因表达，这表明cullln 4A是一种新的调节因子，它同时作用于昼夜节律和新陈代谢。因此，在Roo阶段提出的具体目标3将集中在揭示cullin 4A E3泛素连接酶在调节昼夜节律、胰岛素信号和葡萄糖代谢中的作用。我们希望这项工作将提供一组证据，证明泛素-蛋白天冬氨酸系统在新陈代谢调节中的功能重要性。此外，这项工作可能为确定治疗胰岛素抵抗和糖尿病的新治疗靶点提供新的曙光。