The identification and characterization of a novel circadian ETS factor

新型昼夜节律 ETS 因子的鉴定和表征

基本信息

批准号：
9256765
负责人：
Yong Hoon Kim
金额：
$ 4.86万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256765
关键词：
Attenuated Award Binding Binding Proteins Bioenergetics Biogenesis Biological Biological Assay Biological Clocks Blood Glucose Body Temperature Cardiovascular system Circadian Rhythms Consensus Data Diabetes Mellitus Digestive System Disorders Disease Electron Microscopy Enhancers Epidemic Epidemiologic Studies Epidemiology Exhibits Family Feedback Fellowship Functional disorder GA-binding protein transcription factor Genetic Genetic Transcription Genome Genomics Genus Hippocampus Goals Health Hepatic Hepatocyte Homeostasis Hour Human In Vitro Incidence Institutes Ketones Kidney Diseases Knock-out Lead Link Liver Mass Spectrum Analysis Measures Medical Membrane Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Monitor Mus Obesity Organism Outcome Oxidative Phosphorylation Pattern Pennsylvania Periodicity Phase Phenocopy Physicians Physiological Physiology Post-Translational Protein Processing Prevalence Proteins Proteomics Public Health Recruitment Activity Respiratory physiology Role Scientist Series Serum Sleep Societies Staining method Stains Testing Therapeutic Time Training Programs Transcriptional Regulation Triglycerides Universities Untranslated RNA base career chromatin immunoprecipitation circadian pacemaker comorbidity environmental change expectation fatty acid oxidation functional genomics genome-wide genome-wide analysis genomic data in vivo innovation insight knock-down liver metabolism loss of function medical schools metabolic phenotype neuropsychiatric disorder novel pre-doctoral research study shift work transcription factor

项目摘要

Project Summary This application is for a predoctoral fellowship awarded by the National Institute of Diabetes and Digestive and Kidney Diseases to physician-scientist trainees. The applicant is a trainee of the Medical Scientist Training Program at the Perelman School of Medicine at the University of Pennsylvania. This award would help him achieve his career goal of becoming a physician-scientist investigating the role of circadian rhythms in metabolism. Circadian rhythms are biological clocks that regulate all-encompassing aspects of human physiology. Circadian misalignment is prevalent in the modern society and one of the contributing factors to the rising epidemics of obesity and diabetes in the U.S. and worldwide. In support of this, many epidemiological studies have demonstrated that night shift workers are more likely to have higher BMI and more prone to developing metabolic diseases such as obesity, diabetes, and related cardiovascular comorbidities. While this is an imperative public health issue with increasing significance, we still lack a mechanistic understanding of the relationship between the circadian clock and metabolism. In efforts to better understand the molecular mechanisms linking circadian rhythms to metabolic homeostasis, our lab has undertaken a genome-wide study characterizing how hepatic transcription is regulated in a circadian manner. Reassuringly, we identified several transcription factors known to coordinate specific circadian phases of transcription, such as Rev-erbα and Bmal1. Interestingly, our functional genomic data predicted that a transcription factor from the ETS family regulates a circadian phase of transcription at 7 AM-10 AM. However, there is no ETS factor known to behave in a circadian manner. In this proposal, I provide preliminary proteomic and genomic data suggesting that GABPα is the circadian ETS transcription factor, with potential roles in mitochondrial biogenesis and metabolic homeostasis. This finding raises both mechanistic questions about how GABPα coordinates circadian transcription and the functional role of GABPα in hepatic metabolism. For Aim 1, I will dissect the molecular mechanism of circadian transcriptional control by GABPα using a genetic loss-of-function approach and an unbiased proteomics approach. For Aim 2, I will determine the physiological role of GABPα in hepatic metabolism by measuring physiologic and metabolic parameters and performing functional metabolic assays, ultimately to link molecular, cellular, and metabolic changes with physiological outcomes. These integrative experiments will determine the previously unrecognized circadian role of GABPα in transcriptional regulation and hepatic metabolism. Furthermore, the novel insights gained from this proposal will have both mechanistic and therapeutic implications for how circadian misalignment leads to metabolic dysfunction.

项目概要本申请适用于国家糖尿病与消化和消化研究所授予的博士前奖学金肾脏疾病医师科学家实习生申请人是医学科学家培训的实习生。宾夕法尼亚大学佩雷尔曼医学院的项目对他有帮助。实现他的职业目标，成为一名研究昼夜节律在疾病中的作用的医生科学家昼夜节律是调节人类各个方面的生物钟。昼夜节律失调在现代社会中很普遍，也是造成这一现象的因素之一。许多流行病学研究都支持这一观点。研究表明，夜班工人更有可能拥有较高的体重指数，并且更容易出现发展代谢疾病，如肥胖、糖尿病和相关的心血管合并症。是一个日益重要的紧迫公共卫生问题，但我们仍然缺乏机制认识生物钟和新陈代谢之间的关系努力更好地了解分子。为了将昼夜节律与代谢稳态联系起来，我们的实验室进行了一项全基因组研究令人放心的是，我们确定了肝脏转录如何以昼夜节律方式调节的特征。已知可协调转录的特定昼夜节律阶段的转录因子，例如 Rev-erbα 和 Bmal1.暗示，我们的功能基因组数据预测来自 ETS 家族的转录因子。调节上午 7 点至上午 10 点的转录昼夜节律阶段，但目前尚无已知的 ETS 因子发挥作用。在这个提案中，我提供了初步的蛋白质组学和基因组数据，表明这一点。 GABPα 是昼夜节律 ETS 转录因子，在线粒体生物合成和代谢中具有潜在作用这一发现提出了关于 GABPα 如何协调昼夜节律的两个机制问题。对于目标 1，我将剖析 GABPα 在肝脏代谢中的转录和功能作用。使用遗传功能丧失方法和 GABPα 进行昼夜节律转录控制的机制对于目标 2，我将确定 GABPα 在肝脏中的生理作用。通过测量生理和代谢参数并进行功能代谢测定来进行代谢，最终将分子、细胞和代谢变化与生理结果联系起来。实验将确定 GABPα 在转录调节中先前未被认识的昼夜节律作用此外，从该提案中获得的新见解将具有机械性。以及昼夜节律失调如何导致代谢功能障碍的治疗意义。