Coordinated regulation of mitochondrial and cellular functions by nuclear receptors

项目总结 线粒体是细胞中产生大部分能量的细胞器。在我们对如何调节特定的线粒体途径以适应组织特定的功能和新陈代谢的理解上存在差距。这项拟议的研究的目的是填补这一知识空白，并揭示核受体ERRγ依赖的转录程序在肾脏生理学和疾病中以前未被认识到的作用。在我们大量的初步数据的支持下，我们假设Errγ通过与肾脏特异的转录因子协同控制线粒体和肾脏功能而促进正常的肾功能和肾脏疾病。在具体目标1中，我们将使用一个新的小鼠模型，确定ERRγ在体内维持正常线粒体和肾脏功能中的重要作用。我们还将研究激活ERRγ转录程序是否可以改善肾脏疾病模型的肾功能。在具体目标2中，我们将利用最先进的基因组方法，从机制上确定ERRγ如何调节肾脏线粒体和功能基因。总之，这些研究将通过加强我们对维持线粒体功能的组织特异性机制的理解，揭示新的ERRγ途径在肾功能中的作用以及针对ERRγ的治疗的可能性而产生重大影响。

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.