Transcriptional Control of Mitochondrial Bioenergetic Function

线粒体生物能功能的转录控制

基本信息

批准号：
8884153
负责人：
Pere Puigserver
金额：
$ 9.56万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884153
关键词：
Accounting Adipocytes Adipose tissue Adrenergic Agents Affect Amino Acids Animals Applications Grants Atherosclerosis Automobile Driving Biochemical Biochemical Process Bioenergetics Body Weight Brown Fat Cells Complex Cultured Cells Cyclic AMP Defect Diabetes Mellitus Diet Disease Energy Intake Energy Metabolism Equilibrium Family Fatty acid glycerol esters Gene Expression Genes Genetic Genetic Transcription Goals Health Heating Homeostasis Investigation Laboratories Maintenance Mediating Metabolic Metabolic Diseases Mitochondria Mitochondrial Proteins Molecular Molecular Analysis Mus Muscle Cells Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Hormone Receptors Nutrient Obesity Outcome Study Pathway interactions Phosphorylation Polycomb Preparation Process Proteins Recruitment Activity Regulation Repressor Proteins Respiration Signal Pathway Signal Transduction Site Skeletal Muscle System Testing Tissues Transcription Coactivator Transcriptional Regulation Translating Work YY1 Transcription Factor adrenergic base chromatin protein energy balance feeding gain of function glucose metabolism in vivo lipid metabolism loss of function metabolomics mouse model nuclear respiratory factor oxidation protein complex protein expression research study scaffold skeletal

项目摘要

DESCRIPTION (provided by applicant): Energy expenditure (a major component of body weight) is regulated through a complex regulatory network formed by signaling and transcriptional components that control bioenergetic/metabolic function. Skeletal muscle and beige/brown adipose are key tissues that account for a large fraction of energy expenditure. Adrenergic/cAMP signaling is one of the powerful pathways that affect energy balance and cellular bioenergetics. Defects in components of the signaling/transcriptional and mitochondrial bioenergetic system is sufficient to promote obesity and associated disorders such as type 2 diabetes and atherosclerosis. Importantly, maintenance and activation of mitochondrial bioenergetic function strictly depend on basal and regulated transcription of nuclear genes encoding for mitochondrial proteins. Among the transcriptional regulators of these mitochondrial processes are the PGC1 family of coactivators and transcription factors including Nuclear Respiratory Factors, Hormone Nuclear Receptors and YY1. In the last years, our laboratory has identified the transcription factor YY1 as a key regulator of nuclear mitochondrial genes that has a major impact in mitochondrial bioenergetic capacity, both in cultured cells and in animals. Depending on YY1 phosphorylation at specific sites, phospho-YY1 forms an active complex on mitochondrial genes through recruitment of PGC1�. In contrast, dephospho-YY1 forms a repressor complex through interacting with Polycomb Proteins that suppresses the expression of mitochondrial genes. Importantly, one of the signals that govern YY1-dependent phosphorylation interaction is the cAMP pathway. Based on these findings, the major goal of this proposal is to identify the regulatory mechanisms driving mitochondrial gene expression through YY1 transcriptional complex and to assess the functionality using in-vivo mouse models of obesity and diabetes. We have three Specific Aims: Aim 1 proposes to perform molecular mechanistic analysis of how the YY1 transcriptional complex controls mitochondrial function. Aim 2 is devoted to carry out cellular and functional mitochondrial bioenergetic and metabolic analysis mediated by the YY1 transcriptional protein complex in skeletal and adipose cultured cells. Aim 3 is focused to perform in-vivo metabolic and energetic analysis mediated by the YY1 transcription factor in skeletal muscle and adipose tissues. We will use genetic mouse models with gain and loss-of-function of YY1 in these tissues. The outcomes of these studies will provide the identification of the molecular mechanisms by which the YY1 transcriptional complex regulates mitochondrial bioenergetic capacities and how defects in this complex result in dysregulated mitochondrial function and energy balance. Based on the fact that these pathways are altered in metabolic diseases such as obesity and diabetes, studies proposed in this grant application might translate into potential therapies.

描述（由申请人证明）：通过控制生物能量/代谢功能的信号和转录组件，可以调节体重的主要成分。信号传导/三阶生物能系统是诸如2型糖尿病和动脉粥样硬化的偶然性肥胖症。核受体和YY1。通过募集PGC1。复杂的和使用体内的摩托车和糖尿病的功能。由骨骼和脂肪培养的细胞中的YY1转录蛋白复合物介导。在这些组织中的YY1。该赠款申请可能转化为潜在的疗法。