Mitochondria and metabolism in kidney disease

肾脏疾病中的线粒体和代谢

• 批准号: 10673791
• 负责人: Samir M Parikh
• 金额: $ 24.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673791
• 关键词: Active Biological Transport; Acute; Acute Renal Failure with Renal Papillary Necrosis; Anabolism; Applications Grants; Area; Articulation; Attenuated; Award; Biogenesis; Biology; Cells; Chronic; Chronic Kidney Failure; Cicatrix; Clinical; Collaborations; Data; Development; Drug Compounding; End stage renal failure; Energy Metabolism; Enzyme Inhibitor Drugs; Exhibits; Failure; Fibrosis; Fluid Balance; Funding; Future; Genetic Models; Health; Homeostasis; Hospitalization; Human; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Knowledge; Laboratories; Medicine; Metabolic; Metabolism; Mitochondria; Modeling; Organelles; Outcome; PPAR gamma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Prevention; Probability; Production; Proteins; Public Health; Publications; Quality Control; Renal function; Renal tubule structure; Reperfusion Injury; Reporting; Research; Resistance; Risk; Sodium; Stress; Testing; Therapeutic; Transcriptional Activation; Transgenic Mice; Translations; Tubular formation; United States National Institutes of Health; Work; cell injury; cofactor; design; improved; in vivo; injured; insight; long-term sequelae; new therapeutic target; pharmacologic; precision medicine; prevent; programs; public health relevance; research clinical testing; stressor; success; tool; transcription factor

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.

修改的项目摘要/摘要部分 背景：急性肾脏损伤（AKI）仍然是伯恩的主要全球公共卫生。它的长期后遗症包括慢性和末期肾脏疾病。在该奖项的前两个周期中，我们确定了线粒体生物发生调节剂PGC1是实验AKI结果的确定。独立研究不仅验证了PGC1依赖性的肾脏保护，而且还将其扩展到AKI后的纤维化保护。在最近的周期中，我们确定了PGC1下游肾脏保护的两个候选作用：代谢辅助因子NAD+和转录因子EB（TFEB）。前者对临床测试的不合适性导致了实际AKI患者的观察和试点介入测试的结果。后者协调了一个细胞内程序，以去除受损的蛋白质和细胞器，包括受伤的线粒体，可继发性加重管状细胞损伤。在几种临床适应症中，正在为治疗性线索进行TFEB激活。 假设：我们假设NAD+和TFEB可能会在AKI之后促进长期的肾脏保护。我们建议以两个平行目的评估这一假设。 目的：在AIM 1中，我们将评估NOKNAD+生物合成在两个AKI到纤维化模型中的贡献：缺血 - 再灌注损伤和晶体诱导的肾病。这里的干预措施包括用于临床测试的酶抑制剂化合物和在急性环境中表现出肾脏折射的诱导肾小管转基因小鼠。在AIM 2中，我们将定义AKI后激活TFEB的治疗窗口，作为最初的检查过渡到疤痕。该目标将在同一两种AKI到纤维化模型中采用用于临床测试的药物化合物。 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，并很幸运地与公认的领导者合作以达到这两个目标。有希望的初步数据支持每个目标。了解TFEB的何时何时激活或复制NAD+可能会减弱AKI对纤维化的发展，这不仅可以加深我们对代谢对肾脏健康的影响的基本理解，而且还可以描述未来翻译研究的潜在途径。

项目成果

Energy Metabolism in CKD: Running Low on Fuel.

• DOI: 10.34067/kid.0000000000000231
• 发表时间: 2023-08-01
• 期刊: Kidney360
• 作者: Saade MC;Parikh SM
• 通讯作者: Parikh SM

States of quinolinic acid excess in urine: A systematic review of human studies.

• DOI: 10.3389/fnut.2022.1070435
• 发表时间: 2022
• 期刊: FRONTIERS IN NUTRITION
• 影响因子: 5
• 作者: Saade, Marie Christelle;Clark, Amanda J.;Parikh, Samir M.
• 通讯作者: Parikh, Samir M.

Moving forward in sepsis research.

脓毒症研究取得进展。

• DOI: 10.1164/rccm.201305-0810le
• 发表时间: 2013
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Karumanchi,SAnanth;Parikh,SamirM
• 通讯作者: Parikh,SamirM

NAD+ precursor nutritional supplements sensitize the brain to future ischemic events.

NAD 前体营养补充剂使大脑对未来的缺血事件敏感。

• DOI: 10.1177/0271678x231156500
• 发表时间: 2023
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Qu,Wensheng;Ralto,KennethM;Qin,Tao;Cheng,Yinhong;Zong,Weifeng;Luo,Xiang;Perez-Pinzon,Miguel;Parikh,SamirM;Ayata,Cenk
• 通讯作者: Ayata,Cenk

Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation.

• DOI: 10.1172/jci158096
• 发表时间: 2022-12-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Taguchi, Kensei;Elias, Bertha C.;Sugahara, Sho;Sant, Snehal;Freedman, Benjamin S.;Waikar, Sushrut S.;Pozzi, Ambra;Zent, Roy;Harris, Raymond C.;Parikh, Samir M.;Brooks, Craig R.
• 通讯作者: Brooks, Craig R.