Epigenetic regulation of metabolism by target of rapamycin complex 2

雷帕霉素复合物 2 靶标对代谢的表观遗传调控

• 批准号: 8926980
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 38.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926980
• 关键词: Acetylation; Affect; American; Binding Proteins; Biochemical; Blindness; Blood Glucose; Body Size; Caenorhabditis elegans; Cause of Death; Cell Line; Chromatin; Clinical Endocrinology; Complex; DNA Sequence; Data; Defect; Development; Diabetes Mellitus; Dosage Compensation (Genetics); Elements; Epigenetic Process; Event; Fatty acid glycerol esters; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Glucocorticoids; Goals; Growth; Health; Heart Diseases; Hepatic; Histone Deacetylase; Histones; Human; Hyperglycemia; Insulin; Insulin Resistance; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Lead; Life; Lipids; Liver; Longevity; Lysine; Mediating; Metabolic; Metabolism; Methylation; Methyltransferase; Mus; Non-Insulin-Dependent Diabetes Mellitus; Output; Pathway interactions; Phenotype; Phosphotransferases; Physical condensation; Physiological; Post-Translational Regulation; Prevention; Protein Kinase; RNA Interference; Regulation; Reproduction; Research Personnel; Resistance; Role; Serum; Signal Transduction; Sirolimus; Site; Staging; Stroke; System; Training; Work; base; chromatin remodeling; condensin; design; disability; effective therapy; epigenetic regulation; epigenomics; experience; functional genomics; glucose metabolism; histone modification; insulin sensitivity; insulin signaling; lipid metabolism; mTOR protein; meetings; mutant; professor; programs; success

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) affects more than 25 million Americans and is a leading cause of heart disease, stroke, blindness, and kidney disease. A hallmark of T2D is insulin resistance; however, myriad poorly understood factors contribute to the pathophysiology of insulin resistance. Mounting evidence in humans suggests that life- long insulin resistance may be influenced by epigenetic mechanisms or changes in genomic regulation without alterations in DNA sequence. There is a critical need to better understand fundamental outputs of insulin signaling in order to better target insulin resistance. This project will meet this critical need by uncovering key signaling events downstream of target of rapamycin complex 2 (TORC2), a highly conserved protein kinase critical to the regulation of insulin sensitivity. Mice lacking mammalian TORC2 (mTORC2) in liver develop profound insulin resistance with diabetes-like phenotypes, hyperglycemia and defects in lipid metabolism. Our previous work indicates that TORC2 is a conserved regulator of lipid metabolism as C. elegans TORC2 (CeTORC2) mutants also show defects in lipid metabolism as well as growth, reproduction, and lifespan. Although a major output of TORC2 is activation of the protein kinase Akt, in C. elegans and in mice, there is evidence for additional, important outputs of TORC2 regulating metabolism. Our prior work shows significant similarity in signaling downstream of mTORC2 and CeTORC2, indicating that study of phylogenetically conserved elements of the TORC2 pathway in both systems will illuminate critical, fundamental aspects of insulin signaling. Our preliminary data are the first evidence that a conserved epigenetic pathway is central to the regulation of lipid metabolism, growth, and reproduction by TORC2 in C. elegans. We hypothesize that TORC2 normally activates a program of gene expression to modulate metabolism by communicating with the cellular epigenetic machinery. Our major goal is to elucidate the full spectrum of conserved, TORC2-regulated epigenetic changes that regulate metabolism. In Aim 1, we will use C. elegans genetics and genomics to identify the mechanisms by which CeTORC2-regulated epigenetic changes lead to altered metabolism, and we will use liver specific mTORC2 knockout mice to demonstrate conservation of epigenetic mechanisms acting downstream of the complex. In Aim 2 we will use genomic, biochemical and physiologic approaches in C. elegans and mice to define conserved mechanisms by which TORC2 regulates changes in gene expression via epigenetics. At the conclusion of these studies, we will have identified the major epigenetic mechanisms by which TORC2 regulates metabolism. These findings will have broad implications for study of states of insulin resistance and for futur design of more effective therapies and preventions for T2D, and will provide an inroad to study how lifelong insulin resistance is impacted by heritable changes in chromatin.

描述（由申请人提供）：2型糖尿病（T2 D）影响超过2500万美国人，是心脏病、中风、失明和肾脏疾病的主要原因。T2 D的标志是胰岛素抵抗;然而，无数知之甚少的因素导致胰岛素抵抗的病理生理学。越来越多的人类证据表明，终身胰岛素抵抗可能受到表观遗传机制或基因组调控变化的影响，而不改变DNA序列。迫切需要更好地了解胰岛素信号传导的基本输出，以便更好地靶向胰岛素抵抗。这个项目 将通过揭示雷帕霉素复合物2（TORC 2）靶点下游的关键信号传导事件来满足这一关键需求，TORC 2是一种高度保守的蛋白激酶，对胰岛素敏感性的调节至关重要。肝脏中缺乏哺乳动物TORC 2（mTORC 2）的小鼠会出现严重的胰岛素抵抗，并伴有糖尿病样表型、高血糖症和脂质代谢缺陷。我们的前期工作表明TORC 2与C.秀丽线虫TORC 2（CeTORC 2）突变体还显示出脂质代谢以及生长、繁殖和寿命的缺陷。尽管TORC 2的主要输出是激活蛋白激酶Akt，但在C.在线虫和小鼠中，有证据表明TORC 2调节代谢的额外重要输出。我们先前的工作显示mTORC 2和CeTORC 2下游的信号传导具有显著的相似性，这表明对两个系统中TORC 2通路的遗传保守元件的研究将阐明胰岛素信号传导的关键、基本方面。我们的初步数据是第一个证据，保守的表观遗传途径是中央的调节脂质代谢，生长和繁殖的TORC 2在C。优美的我们假设TORC 2通常激活基因表达程序，通过与细胞表观遗传机制沟通来调节代谢。我们的主要目标是阐明保守的，TORC 2调节的表观遗传变化，调节代谢的全谱。在目标1中，我们将使用C。elegans遗传学和基因组学来确定CeTORC 2调节的表观遗传变化导致代谢改变的机制，我们将使用肝脏特异性mTORC 2敲除小鼠来证明作用于复合物下游的表观遗传机制的保守性。在目标2中，我们将使用基因组，生物化学和生理学方法在C。elegans和小鼠来定义TORC 2通过表观遗传学调节基因表达变化的保守机制。在这些研究的结论中，我们将确定TORC 2调节代谢的主要表观遗传机制。这些发现将对胰岛素抵抗状态的研究以及未来设计更有效的T2 D治疗和预防方法具有广泛的意义，并将为研究终身胰岛素抵抗如何受到染色质遗传变化的影响提供进展。