Coordinated regulation of mitochondrial and cellular functions by nuclear receptors

核受体对线粒体和细胞功能的协调调节

基本信息

批准号：
9897554
负责人：
Liming Pei
金额：
$ 37.75万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897554
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adult Aging Agonist Alzheimer&apos s Disease Binding Binding Sites Biological Assay Biology Cardiac Cardiac Myocytes Cell physiology Cells ChIP-seq Chronic Kidney Failure Complex Cystic kidney Data Diabetes Mellitus Disease Disease model Epithelial Cells Estrogen Nuclear Receptor Folic Acid Gene Expression Genes Genetic Transcription Genome Genomic approach Glycolysis Goals Health Heart Diseases Human Kidney Kidney Diseases Knockout Mice Knowledge Ligands Limes Link Malignant Neoplasms Mediating Metabolism Mitochondria Mus Mutation Neurons Nuclear Receptors Obesity Organelles Oxidative Phosphorylation PPAR alpha PPAR gamma Parkinson Disease Pathology Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmacology Physiology Proteins Quantitative Trait Loci Regulation Renal function Reporter Research Role Scientist Site Testing Tissues Transcriptional Regulation cell type chromatin immunoprecipitation estrogen-related receptor fatty acid oxidation improved in vivo kidney dysfunction knock-down mitochondrial dysfunction mouse model novel nuclear respiratory factor programs renal epithelium small hairpin RNA targeted treatment transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Mitochondria are organelles that generate most of the energy in the cell. There is a gap in our understanding of how specific mitochondrial pathways are regulated to suit tissue-specific function and metabolism. The goal of this proposed research is to fill this knowledge gap and to reveal a previously unrecognized role for a nuclear receptor ERRγ-dependent transcriptional program in kidney physiology and disease. Supported by our extensive preliminary data, we hypothesize that ERRγ contributes to normal kidney function and renal disease by controlling mitochondrial and renal function in cooperation with kidney-specific transcription factors. In Specific Aim 1, we will determine the essential role of ERRγ in maintaining normal mitochondrial and renal function in vivo, using a novel mouse model. We will also investigate whether activation of the ERRγ transcriptional program can improve kidney function in kidney disease models. In Specific Aim 2, we will determine mechanistically how ERRγ regulates renal mitochondrial and functional genes, employing state-of-the-art genomic approaches. Together, these studies will have a significant impact by enhancing our understanding of tissue specific mechanisms for maintaining mitochondrial function, and revealing a novel ERRγ pathway in kidney function and the potential for therapies targeting ERRγ.

项目概要线粒体是细胞中产生大部分能量的细胞器，我们对如何调节特定线粒体途径以适应组织特异性功能和代谢的理解存在差距。这项研究的目标是填补这一知识空白。揭示了核受体 ERRγ 依赖性转录程序在肾脏生理学和疾病中以前未被认识的作用。根据我们广泛的初步数据的支持，我们认为 ERRγ 通过控制线粒体和肾功能来促进正常肾功能和肾脏疾病。在具体目标 1 中，我们将使用一种新型小鼠模型来确定 ERRγ 在维持正常线粒体和肾功能中的重要作用，我们还将研究 ERRγ 转录程序的激活是否可以改善。在具体目标 2 中，我们将采用最先进的基因组方法从机制上确定 ERRγ 如何调节肾线粒体和功能基因，这些研究将通过增强我们对肾功能的理解而产生重大影响。维持线粒体功能的组织特异性机制，揭示肾功能中的新 ERRγ 途径以及针对 ERRγ 的治疗潜力。