Stimulation of Mitochondrial Biogenesis with 5-HT Receptor Agonists

描述（由申请方提供）：急性肾损伤（阿基）是一种发病率和死亡率显著的快速发病疾病，影响高达5%的长期住院患者。大多数阿基病例由肾缺血/再灌注（I/R）或急性药物或毒物暴露引起。治疗人类阿基的治疗策略的开发在很大程度上是不成功的，阿基导致的死亡率几十年来保持不变。因此，开发更成功的疗法需要检查新的靶点。已经证明，暴露于急性氧化剂损伤的肾近端小管细胞，如在急性I/R或毒物暴露中发现的，表现出严重的线粒体功能障碍。已经进一步证明，这些细胞中线粒体功能的恢复与细胞功能的恢复在时间上相关，并且线粒体功能的恢复与过氧化物酶体增殖物受体-3-共激活因子-11（PGC-11）（线粒体生物发生的“主调节因子”）的表达在时间上相关。我们的实验室最近证明，5-HT 2受体激动剂通过增加PGC-11的表达来刺激体外线粒体生物合成。我们首先试图研究5-HT 2受体激活和PGC-11表达之间的信号通路，并在动物模型中验证我们的体外数据。然后，我们打算测试我们的假设，即5-HT 2受体激动剂将诱导线粒体生物合成，并促进急性I/R损伤后的肾功能恢复。具体目的：1）阐明线粒体生物合成的5-HT 2信号通路。2)确定小鼠肾脏线粒体生物合成的5-HT 2信号通路。3)确定5-HT 2激动剂对I/R损伤后肾功能恢复的影响。研究方法：第一个目标将通过使用药理学抑制剂来实现，该抑制剂用于信号传导途径酶，该信号传导途径酶被提议参与5-HT 2受体激动剂对线粒体生物合成的刺激。第二个目标将通过使用siRNA“敲低”小鼠中阐明的信号传导途径的组分并测量作为5-HT 2受体激动剂治疗的结果的线粒体生物发生来实现。第三个目的将通过使小鼠经受I/R急性肾损伤模型并用5-HT 2受体激动剂治疗它们来实现。在存在和不存在这些激动剂的情况下，将监测这些小鼠的肾功能改善。目标：进一步了解5-HT 2受体激动剂在刺激线粒体生物合成中的作用和信号通路，并探索其作为治疗急性肾损伤的新疗法的有效性。与机构的相关性：毒物暴露是急性肾损伤发病机制中的一个重要因素;这些毒物可能是有意施用的，如肾毒性化疗药物，也可能是无意引入的，如环境重金属暴露。这项工作旨在研究5-HT 2受体激动剂在治疗这种急性疾病状态中的有用性。 公共卫生相关性：急性肾损伤是一种严重的疾病状态，影响所有长期住院患者的5%。治疗人类阿基的治疗策略的开发在很大程度上是不成功的，几十年来阿基导致的死亡人数保持不变。该项目旨在研究5-羟色胺受体激活在治疗阿基中的机制和有用性，希望激活5-羟色胺受体的药物将为患有这种严重疾病的患者提供新的和更好的治疗选择。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a rapid-onset disease with significant morbidity and mortality that affects up to 5% of long-term hospital patients. Most cases of AKI result from renal ischemia/reperfusion (I/R) or acute drug or toxicant exposure. The development of therapeutic strategies to treat AKI in humans has been largely unsuccessful and the mortality resulting from AKI has remained unchanged for several decades. Therefore, the development of more successful therapies necessitates the examination of novel targets. It has been demonstrated that renal proximal tubule cells exposed to acute oxidant injury, such as that found in acute I/R or toxicant exposure, exhibit serious mitochondrial dysfunction. It has been further demonstrated that the recovery of mitochondrial function in these cells is temporally related to recovery of cellular function, and that the recovery of mitochondrial function is temporally related to the expression of peroxisome-proliferator- receptor-3-coactivator-11 (PGC-11), the "master regulator" of mitochondrial biogenesis. Our lab has recently demonstrated that 5-HT2 receptor agonists stimulate mitochondrial biogenesis in vitro by increasing the expression of PGC-11. We first seek to examine the signaling pathway between 5-HT2 receptor activation and PGC-11 expression and to verify our in vitro data in an animal model. We then intend to test our hypothesis that 5-HT2 receptor agonists will induce mitochondrial biogenesis and promote recovery of kidney function after in an animal model of acute I/R injury. Specific Aims: 1) Elucidate the 5-HT2 signaling pathway of mitochondrial biogenesis. 2) Determine the 5-HT2 signaling pathway of renal mitochondrial biogenesis in mice. 3) Determine the effect of 5-HT2 agonists on the recovery of renal function following I/R injury. Methods: The first aim will be accomplished by using pharmacological inhibitors to signaling pathway enzymes proposed to be involved in the stimulation of mitochondrial biogenesis by 5-HT2 receptor agonists. The second aim will be accomplished by "knocking down" components of the elucidated signaling pathway in mice using siRNA and measuring mitochondrial biogenesis as a result of 5-HT2 receptor agonist treatment. The third aim will be performed by subjecting mice to a model of I/R acute kidney injury and treating them with 5-HT2 receptor agonists. These mice will be monitored for improvements in kidney function in the presence and absence of these agonists. Goal: To further understand the role and signaling pathway of 5-HT2 receptor agonists in stimulating mitochondrial biogenesis and to probe their usefulness as novel therapeutics to treat acute kidney injury. Relevance to agency: Toxicant exposure is a significant culprit in the pathogenesis of acute kidney injury; these toxicants may be intentionally administered, such as nephrotoxic chemotherapeutics, or unintentionally introduced, such as in the case of environmental heavy metal exposure. This work seeks to examine the usefulness of 5-HT2 receptor agonists in the treatment of this acute disease state. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a serious disease state affecting up to 5% of all long-term hospital patients. The development of therapeutic strategies to treat AKI in humans has been largely unsuccessful and the number of deaths resulting from AKI has remained unchanged for several decades. This project seeks to examine the mechanism and usefulness of serotonin receptor activation in the treatment of AKI, with the hope that agents that activate serotonin receptors will offer new and better treatment options for patients with this serious disease.