Mitochondrial biogenesis in kidney disease

描述（由申请人提供）：急性肾损伤（AKI）是住院患者的主要并发症，肾缺血是主要危险因素。对缺血后肾功能障碍机制的深入研究尚未转化为新的治疗方法，部分原因是不同形式的缺血可能涉及不重叠的分子途径。理由：PGC-1a是线粒体生物发生的调节因子，在近端小管中大量表达，在败血症和缺血再灌注损伤的早期被抑制，在这两种情况下，从近端小管中基因缺失会加剧肾功能。人近端小管细胞通过抑制PGC-1a的下游效应物和减少氧气消耗来响应炎症介质，这种变化被PGC-1a的强制表达逆转。假设：本提案将验证PGC-1a抑制可能是两种缺血性AKI（败血症和缺血再灌注损伤（IRI））中肾功能恶化的共同机制。目的：第一个目的是研究炎症介质抑制人近端小管细胞中PGC-1a表达的机制。第二个目标将使用近端管PGC-1a敲除小鼠的脓毒症和IRI模型来阐明PGC-1a的关键下游效应，这些效应可能在这两种形式的AKI中是独特的或共有的。第三个目标将探讨PGC- 1a近端小管诱导是否可以通过在野生型、全局型和小管特异性敲除小鼠中应用药物诱导剂来改善这些形式的AKI。研究设计：该设计提供功能损失和功能获得实验，以检查PGC-1a的上游调节因子和下游效应因子。实验设计将整合细胞和活体动物实验、成像模式和生化研究的发现，使用严格的遗传工具来解决核心假设。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a major complication for hospitalized patients, and renal ischemia is a predominant risk factor. Intensive research into mechanisms underlying renal dysfunction following ischemia have not translated to new therapies, in part because different forms of ischemia may involve non- overlapping molecular pathways. RATIONALE: PGC-1a, a regulator of mitochondrial biogenesis, is heavily expressed in the proximal tubule, becomes suppressed early during sepsis and ischemia-reperfusion injury, and in both situations, exacerbates renal function when genetically deleted from the proximal tubule. Human proximal tubular cells respond to inflammatory mediators by suppressing downstream effectors of PGC-1a and diminishing oxygen consumption, changes reversed by forced expression of PGC-1a. HYPOTHESIS: This proposal will test the hypothesis that suppression of PGC-1a may be a shared mechanism that exacerbates renal function in two forms of ischemic AKI, sepsis and ischemia-reperfusion injury (IRI). AIMS: The first aim will investigate mechanisms that enable inflammatory mediators to suppress PGC-1a expression in primary human proximal tubular cells. The second aim will use models of sepsis and IRI in proximal tubular PGC-1a knockout mice to elucidate critical downstream effectors of PGC-1a that may be unique or shared in these two forms of AKI. The third aim will ask whether proximal tubular induction of PGC- 1a can ameliorate these forms of AKI by applying pharmaceutical inducers in wildtype, global and tubule- specific knockout mice. RESEARCH DESIGN: The design offers loss- and gain-of-function experiments to examine upstream regulators and downstream effectors of PGC-1a. The experimental design will integrate findings across cellular and live animal experiments, imaging modalities and biochemical studies, using stringent genetic tools to address the core hypothesis.