Coordinated regulation of mitochondrial and cellular functions by nuclear receptors

项目摘要 线粒体是产生细胞中大部分能量的细胞器。我们对特定线粒体通路如何调节以适应组织特异性功能和代谢的理解存在差距。这项拟议研究的目标是填补这一知识空白，并揭示核受体ERRγ依赖性转录程序在肾脏生理学和疾病中的先前未被认识的作用。在我们广泛的初步数据的支持下，我们假设ERRγ通过与肾脏特异性转录因子合作控制线粒体和肾脏功能而促进正常肾功能和肾脏疾病。在具体目标1中，我们将使用一种新的小鼠模型确定ERRγ在体内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肾脏疾病模型中的肾功能。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如何调节肾脏线粒体和功能基因。总之，这些研究将通过增强我们对维持线粒体功能的组织特异性机制的理解，并揭示肾功能中的新ERRγ途径和靶向ERRγ治疗的潜力，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.