Mitochondria and metabolism in kidney disease

修改项目摘要/摘要部分 背景：急性肾损伤（阿基）仍然是全球主要的公共卫生负担。其长期后遗症包括慢性和终末期肾病。在该奖项的前两个周期中，我们已经确定线粒体生物发生调节剂PGC 1 β是实验性阿基结果的决定因素。独立研究不仅证实了PGC 1 β依赖性肾保护作用，而且还将其扩展到阿基后的纤维化保护。在最近的周期中，我们确定了PGC 1 β下游的两个肾保护候选效应子：代谢辅因子NAD+和转录因子EB（TFEB）。前者对临床试验的顺从性在实际阿基患者中的观察性和试点干预性试验中取得了令人鼓舞的结果。 后者协调细胞内程序以去除受损的蛋白质和细胞器，包括可继发性加剧肾小管细胞损伤的受损线粒体。TFEB活化正在几种临床适应症中用于治疗性线粒体自噬。 假设：我们假设NAD+和TFEB可以促进阿基后的长期肾脏保护。我们建议在两个平行的目标来评估这一假设。 目标：在目的1中，我们将评估在两种AKI-纤维化模型中NAD+从头生物合成的贡献：缺血-再灌注损伤和晶体诱导的肾病。这里的干预措施包括正在开发用于临床试验的酶抑制剂化合物和在急性环境中表现出肾保护作用的诱导性肾小管转基因小鼠。在目标2中，我们将定义阿基后TFEB激活的治疗窗口，因为初始损伤过渡到瘢痕形成。该目标将应用正在开发的药物化合物，用于在相同的两种AKI-纤维化模型中进行临床试验。 结论：我们的长期目标是应用代谢见解来改善肾脏健康。我们已经开发了必要的工具，并有幸与这两个目标的公认领导者合作。有希望的初步数据支持每个目标。了解TFEB的激活或NAD+的补充何时以及在何种情况下可以减弱阿基向纤维化的进展，不仅可以加深我们对代谢对肾脏健康影响的基本理解，而且还可以为未来的转化研究描绘潜在的途径。

Modified Project Summary/Abstract Section BACKGROUND: Acute kidney injury (AKI) remains a major global public health burden. Its long-term sequelae include chronic and end-stage kidney disease. Over the first two cycles of this award, we have identified the mitochondrial biogenesis regulator PGC1 as a determinant of experimental AKI outcomes. Independent studies have not only verified PGC1-dependent renoprotection, but also extended this to protection against fibrosis following AKI. In the most recent cycle, we identified two candidate effectors of renoprotection downstream of PGC1: the metabolic cofactor NAD+ and the transcription factor EB (TFEB). The former’s amenability to clinical testing has resulted in encouraging results from observational and pilot interventional testing among actual AKI patients. The latter coordinates an intracellular program to remove damaged proteins and organelles, including injured mitochondria that can secondarily exacerbate tubular cell injury. TFEB activation is being pursued for therapeutic mitophagy in several clinical indications. HYPOTHESIS: We hypothesize that NAD+ and TFEB may promote long-term kidney protection following AKI. We propose to evaluate this hypothesis in two parallel aims. AIMS: In Aim 1, we will evaluate the contribution of de novo NAD+ biosynthesis in two AKI-to-fibrosis models: ischemia-reperfusion injury and crystal-induced nephropathy. The interventions here include an enzyme inhibitor compound being developed for clinical testing and an inducible renal tubular transgenic mouse that exhibits renoprotection in an acute setting. In Aim 2, we will define therapeutic windows for activation of TFEB after AKI as the initial insult transitions to scarring. This Aim will apply a pharmaceutical compound being developed for clinical testing in the same two models of AKI-to-fibrosis. CONCLUSION: Our long-term objective is to apply metabolic insights to improve renal health. We have developed the necessary tools and are fortunate to collaborate with recognized leaders for both Aims. Promising preliminary data supports each Aim. Understanding when and in what contexts activation of TFEB or repletion of NAD+ may attenuate AKI’s progression to fibrosis may not only deepen our fundamental understanding of metabolism’s impact on renal health, but also delineate potential avenues for future translational inquiry.