Mitochondria Functions Modified by Sulfotransferase 1C2

磺基转移酶 1C2 修饰的线粒体功能

• 批准号: 10230976
• 负责人: ROBERT L BACALLAO
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230976
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Aging; Attenuated; Biochemical; Caring; Cell Death; Cellular Metabolic Process; Cholecalciferol; Cholesterol; Clinical; Complex; Consomic Strain; Data; Down-Regulation; Energy Supply; Event; Experimental Models; FDA approved; Gene Delivery; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Health Care Costs; Hemorrhage; Hospitalization; Hypotension; Hypoxia; Impairment; Incidence; Injury; Ischemia; Ischemic Preconditioning; Kidney; Kidney Diseases; Label; Mass Spectrum Analysis; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Potentials; Messenger RNA; Mitochondria; Modality; Modeling; Nephrology; Norway; Oxygen saturation measurement; Pathologic; Pathway interactions; Patients; Phosphorylation; Physiological; Physiology; Plasmids; Population; Predisposition; Preventive therapy; Process; Production; Proteins; Proteomics; Rat Strains; Rattus norvegicus; Recommendation; Renal function; Reperfusion Injury; Resistance; Respiration; Rodent; Role; Sepsis; Severities; Structure; Syndrome; Testing; Therapeutic Intervention; Toxin; Water; Work; base; cholesteryl sulfate; cost; curative treatments; experimental study; fluorescence lifetime imaging; free radical oxygen; genetic resistance; genetic strain; hemodynamics; ischemic injury; laurdan; mitochondrial membrane; mortality; novel strategies; novel therapeutics; oxidation; preconditioning; prevent; receptor; respiratory; sulfotransferase; targeted treatment; therapeutic target

Acute kidney injury (AKI) is the most common renal disease requiring hospitalization and is associated with significant mortality. There remains no reliable treatment modality for acute kidney injury. In the setting of ischemia or hypoxic injury, early alterations in mitochondrial structure impair cellular energetics, activate cell death pathways, increase oxygen free radical generation and may influence renal hemodynamics. Different models of naturally or experimentally induced resistance to ischemic injury may help to identify biochemical, cellular and physiological events underlying the injury process and provide potential targets for therapeutic intervention. Our prior work uncovered a unique, unanticipated role for sulfotransferase 1C2 (SULT1C2) in changing mitochondria physiology to confer protection against ischemic injury. Since we found SULT1C2 is highly up-regulated in proteomic screens of mitochondria isolated from ischemia-preconditioned kidneys, we tested whether kidneys transduced with plasmids bearing SULT1C2 are resistant to ischemia preconditioning. The goal of this proposal is to delineate the extent of the contribution that SULT1C2 makes to altered cell metabolism resulting in an ischemia preconditioned state. We will test the hypothesis that the mitochondria adaptation due to ischemia preconditioning is due in part to direct action of sulfotransferase 1C2 on mitochondria function brought about by changing cholesterol sulfate levels in mitochondria membranes. In these studies, we will utilize two different models of resistance to AKI; 1) a genetic model of the Brown Norway rat and Brown Norway derived consomic strains of rats, and 2) a model of experimentally induced ischemic preconditioning. Studies in specific objective 1 will test the hypothesis that sulfotransferase 1C2 changes mitochondria respirome composition and physiology due to changes in membrane lipid organization. These experiments will utilize a proteomic approach of label-free-quantitative mass spectroscopy to identify biochemical similarities in different models of resistance. Specific aim 2 will test the hypothesis that sulfotransferase 1C2 requires mitochondria receptors to convert cholesterol to cholesterol sulfate. Lastly aim 3 will test the hypothesis that inhibition of sulfotransferase 1C2 or down-regulation of sulfotransferase 1C2 markedly attenuates cellular protection against ischemia reperfusion injury. These studies will investigate post- ischemic mitochondria respiratory capacity, mitochondrial polarization, renal hemodynamics and renal function protection. Overall, the proposed studies will help provide an understanding of cytoprotective strategies and identify potential therapeutic targets to manage the severity of AKI.

急性肾脏损伤（AKI）是需要住院的最常见的肾脏疾病，与 重大死亡率。急性肾脏损伤仍然没有可靠的治疗方式。在 缺血或低氧损伤，线粒体结构的早期改变会损害细胞能量，激活细胞 死亡途径，增加氧气自由基产生，并可能影响肾脏血流动力学。不同的 自然或通过实验引起的对缺血性损伤的抗性的模型可能有助于鉴定生化， 损伤过程为基础的细胞和生理事件，并为治疗提供了潜在的靶标 干涉。我们先前的工作发现了硫代转移酶1C2（Sult1c2）的独特，意外的作用 改变线粒体生理学以防止缺血性损伤。因为我们发现sult1c2是 在从缺血基础的肾脏分离的线粒体的蛋白质组学筛选中高度上调，我们 测试了用带有Sult1c2质粒转导的肾脏是否耐缺血预处理。 该提案的目的是描述Sult1c2对细胞更改的贡献的程度 代谢导致缺血预处理状态。我们将测试线粒体的假设 由于缺血预处理引起的适应部分是由于硫代转移酶1C2在上的直接作用。 线粒体硫酸胆固醇水平在线粒体膜中带来的线粒体功能。 在这些研究中，我们将利用两种对AKI的抗性模型。 1）棕色的遗传模型 挪威大鼠和棕色挪威衍生的大鼠菌株，以及2）实验诱导的模型 缺血性预处理。特定目标1中的研究将检验硫代转移酶1C2的假设 由于膜脂质组织的变化而改变线粒体呼吸组成和生理学。 这些实验将利用无标记 - 定量质谱的蛋白质组学方法来鉴定 不同模型的耐药模型中的生化相似性。具体目标2将检验以下假设 硫代转移酶1C2需要线粒体受体将胆固醇转化为硫酸胆固醇。最后是目标3 将检验以下假设，即抑制磺胺转移酶1C2或磺胺转移酶1C2的下调 明显地减弱了细胞防止缺血再灌注损伤。这些研究将调查 - 缺血性线粒体呼吸能力，线粒体极化，肾脏血液动力学和肾功能 保护。总体而言，拟议的研究将有助于了解细胞保护策略和 确定潜在的治疗靶标，以管理AKI的严重性。