Mitochondria and metabolism in kidney disease

修改后的项目摘要/摘要部分 背景：急性肾损伤(AKI)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控因子Pgc1是实验AKI结果的决定因素。独立研究不仅证实了Pgc1依赖的肾脏保护作用，而且还将其扩展到预防急性心肌梗死后的纤维化。在最近的周期中，我们确定了两个候选的肾保护效应因子：代谢辅助因子NAD和转录因子EB()。前者对临床测试的适应性导致了在实际AKI患者中进行的观察性和试验性干预测试的令人鼓舞的结果。后者协调细胞内的程序，以移除受损的蛋白质和细胞器，包括受损的线粒体，这可能会继而加剧肾小管细胞的损伤。在几个临床适应症中，TFEB激活正被用于治疗性有丝分裂。 假设：我们假设NAD和TFEB可能促进AKI后的长期肾脏保护。我们建议从两个平行的目标来评估这一假设。 目的：在目标1中，我们将评估NAD生物合成在两种AKI-纤维化模型中的作用：缺血-再灌注损伤和结晶性肾病。这里的干预措施包括正在开发的用于临床测试的酶抑制剂化合物，以及在急性环境中表现出肾保护作用的可诱导肾小管转基因小鼠。在目标2中，我们将AKI后激活TFEB的治疗窗口定义为最初的创伤过渡到瘢痕形成。这一目标将应用于正在开发的用于临床测试的药物化合物，用于相同的两种AKI到纤维化模型。 结论：我们的长期目标是应用代谢洞察力来改善肾脏健康。我们已经开发了必要的工具，并有幸与公认的领导人合作，以实现这两个目标。前景看好的初步数据支持每个目标。了解何时以及在什么情况下激活TFEB或重复NAD可以减缓AKI的纤维化进展，不仅可以加深我们对代谢对肾脏健康的影响的基本理解，还可以为未来的翻译研究勾勒出潜在的途径。

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.