Mitochondrial biogenesis in kidney disease

描述（由申请方提供）：急性肾损伤（阿基）是住院患者的主要并发症，肾缺血是主要风险因素。对缺血后肾功能不全潜在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非重叠的分子途径。基本原理：PGC-1a是一种线粒体生物发生的调节因子，在近端小管中大量表达，在脓毒症和缺血再灌注损伤期间早期受到抑制，并且在这两种情况下，当从近端小管中基因删除时，会加剧肾功能。人近端肾小管细胞通过抑制PGC-1a的下游效应物和减少氧消耗来响应炎症介质，PGC-1a的强制表达逆转了这种变化。假设：该提案将检验以下假设：PGC-1a的抑制可能是在两种形式的缺血性阿基、脓毒症和缺血再灌注损伤（IRI）中加重肾功能的共同机制。目标：第一个目标将调查机制，使炎症介质抑制PGC-1a在原代人近端肾小管细胞的表达。第二个目标将使用近端肾小管PGC-1a基因敲除小鼠的脓毒症和IRI模型，以阐明PGC-1a的关键下游效应物，这些效应物在这两种形式的阿基中可能是独特的或共有的。第三个目的将询问PGC- 1a的近端小管诱导是否可以通过在野生型、整体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阿基。研究设计：该设计提供了功能丧失和获得实验，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，成像方式和生化研究的结果，使用严格的遗传工具来解决核心假设。公共卫生相关性：败血症和缺血再灌注损伤是住院患者缺血性肾损伤的主要原因。PGC-1a在两种实验模型中的作用表明，这种分子可能参与缺血性肾损伤的一般机制。了解PGC- 1a在这些环境中如何受到抑制以及PGC-1a的效应物最关键，不仅有可能促进我们对肾脏生物学的基本理解，而且还可能转化为这种常见和病态疾病的新治疗可能性。 公共卫生相关性：急性肾损伤（阿基）是一种昂贵且病态的并发症，影响所有住院患者的2-7%。没有有效的治疗方法来解决这个问题，我们发现，随着阿基的发展，肾脏内的细胞能量生产工厂-线粒体受到损伤，并且由称为PGC-1 α的基因控制的独特分子途径有助于肾脏重建其线粒体，因为它试图从阿基中恢复。在这个应用程序中，我们将询问这种新的见解是否有潜力转化为受这种疾病折磨的人的一流疗法。

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. PUBLIC HEALTH RELEVANCE: Sepsis and ischemia-reperfusion injury are major contributors to ischemic renal injury suffered by hospitalized patients. The effect of PGC-1a in experimental models of both suggests that this molecule may participate in a general mechanism of ischemic renal injury. Understanding how PGC- 1a becomes suppressed in these settings and what effectors of PGC-1a are most critical has potential not only to advance our fundamental understanding of renal biology, but also to translate into novel therapeutic possibilities for this common and morbid disease. PUBLIC HEALTH RELEVANCE: Acute kidney Injury (AKI) is a costly and morbid complication that affects 2-7% of all hospitalized patients. No effective therapies exist to combat this problem We have found that mitochondria-the energy-producing factories of the cell-within the kidney become injured as AKI develops and that a unique molecular pathway governed by a gene called PGC-1alpha helps the kidney rebuild its mitochondria as it attempts to recover from AKI. In this application, we will ask whether this new insight has potential to translate into a first-i-class therapy for people afflicted by this disorder.