Mitochondrial Biogenesis Promotes Recovery from Oxidant Injury

描述（由申请人提供）：该项目的目标是确定加速急性器官衰竭恢复的治疗方法。由缺血/再灌注（I/R）、药物、毒物和创伤诱导的细胞损伤和死亡导致包括肾脏在内的许多器官的衰竭。线粒体功能障碍是这些损伤的常见后果，也是细胞损伤和死亡的主要机制。急性肾损伤（阿基）领域的大多数研究都集中在引发肾功能不全的事件上，但缺乏治疗药物。这表明，更成功的疗法需要检查新的靶点，并专注于加速阿基的恢复。我们最近确定，经受双侧肾I/R诱导的阿基的小鼠和经受肌红蛋白尿性阿基的大鼠在损伤后24小时具有升高的血清肌酐，其在损伤后6天内部分恢复。线粒体电子传递链和ATP合成蛋白在损伤后24小时耗尽，并且在六天内没有恢复，揭示了阿基后线粒体功能的持续破坏。因此，我们提出，增加线粒体生物合成（MB）的治疗将促进阿基的恢复。作为我们鉴定诱导MB的药物的药物发现计划的一部分，我们鉴定了福莫特罗，一种特异性长效β 2-肾上腺素能受体激动剂（β 2-AR），是肾近端小管细胞（RPTC）中MB的强效和有效诱导剂。福莫特罗是FDA批准的用于治疗哮喘的药物。其他研究显示，低剂量福莫特罗可诱导小鼠肾脏中的MB。然而，尚未阐明福莫特罗诱导MB的信号通路。最后，初步研究表明，在I/R后24小时，当建立肾功能障碍时，用福莫特罗治疗的小鼠加速了[线粒体和]肾功能的恢复。我们假设福莫特罗通过b2-AR诱导MB，福莫特罗加速小鼠I/R后[线粒体和]肾功能的恢复。为了解决这一假设，我们提出了以下特定目的：1）阐明RPTC中福莫特罗诱导MB [和RPTC中氧化损伤后]的信号传导途径，2）确定福莫特罗诱导MB在小鼠中的疗效、效价和机制，3）阐明福莫特罗对体内肾I/R诱导阿基后线粒体和肾功能恢复的影响。这些实验的成功完成将通过以下方式推进该领域：1）鉴定通过b2-AR诱导MB的精确信号传导途径，2）证明刺激线粒体功能的恢复导致肾功能恢复的加速，以及3）为阿基提供快速的临床可转化治疗。

DESCRIPTION (provided by applicant): The goal of this project is to identify therapeutics that accelerate the recovery from acute organ failure. Cell injury and death induced by ischemia/reperfusion (I/R), drugs, toxicants, and trauma lead to failure of many organs, including the kidney. Mitochondrial dysfunction is a common consequence of these insults and a major mechanism of cell injury and death. The majority of research in the field of acute kidney injury (AKI) has focused on the events that initiate renal dysfunction, but therapeutic agents are lacking. This suggests that more successful therapies require the examination of new targets and a focus on accelerating recovery from AKI. We recently determined that mice subjected to bilateral renal I/R induced AKI and rats subjected to myoglobinuric AKI had elevated serum creatinine 24 h after injury which partially recovered over six days post- injury. Mitochondrial electron transport chain and ATP synthesis proteins were depleted 24 h after injury and did not recover over six days, revealing persistent disruption of mitochondrial function after AKI. Consequently, we propose that therapeutics that increase mitochondrial biogenesis (MB) will promote recovery from AKI. As part of our drug discovery program to identify drugs that induce MB we identified formoterol, a specific long- acting b2-adrenergic receptor agonist (b2-AR), was a potent and efficacious inducer of MB in renal proximal tubular cells (RPTC). Formoterol is a FDA-approved drug used to treat asthma. Additional studies revealed that formoterol induced MB in the kidneys of mice at a low dose. However, the signaling pathway(s) responsible for formoterol-induced MB has not been elucidated. Finally, preliminary studies demonstrated that mice treated with formoterol 24 h after I/R, when renal dysfunction is established, accelerated recovery of [mitochondrial and] renal function. We hypothesize that formoterol induces MB through the b2-AR and that formoterol accelerates recovery of [mitochondrial and] renal function following I/R in mice. To address this hypothesis we propose the following Specific Aims: 1) Elucidate the signaling pathway(s) of formoterol- induced MB in RPTC [and following oxidant injury in RPTC], 2) Determine efficacy, potency and mechanism of formoterol-induced MB in mice, and 3) Elucidate the effects of formoterol on the recovery of mitochondrial and renal function following renal I/R-induced AKI in vivo. Successful completion of these experiments will advance the field by 1) identifying the precise signaling pathway that induces MB through b2-AR, 2) demonstrating that stimulating the recovery of mitochondrial function results in the acceleration of recovery of renal function, and 3) providing a rapidly clinically translatable treatment for AKI.