Metabolic Reprogramming in Acute Kidney Injury

急性肾损伤中的代谢重编程

基本信息

批准号：
8930970
负责人：
Volker Hans Haase
金额：
$ 23.74万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930970
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Animal Model Antioxidants Biochemical Biogenesis Biological Biological Assay Biological Process Brain Hypoxia-Ischemia Chronic Chronic Kidney Failure Clinical Cre-LoxP Critical Care Critiques Cytoprotection Energy Metabolism Epithelial Epithelial Cells Epithelium Erythropoiesis Erythropoietin Event Functional disorder Genetic Genetically Engineered Mouse Glutamine Grant Health Homologous Gene Hydroxylation Hypoxia Hypoxia Inducible Factor Image In Vitro Individual Inflammatory Injury Intensive Care Iron Kidney Laboratories Lead Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Molecular Genetics Natural regeneration Outcome Oxygen Oxygenases Pathway interactions Physiology Play Prevention Procollagen-Proline Dioxygenase Production Proline Proteins Regulation Renal Interstitial Cell Reperfusion Injury Resolution Respiration Role Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization System Tetracyclines Therapeutic Therapeutic Intervention Tubular formation Work alpha ketoglutarate angiogenesis bHLH-PAS factor HLF base cell type clinical care glucose metabolism hypoxia inducible factor 1 improved in vivo inhibitor/antagonist injured insight macromolecule metabolic abnormality assessment mortality pre-clinical programs renal epithelium renal hypoxia renal ischemia renal ischemia/hypoxia repaired response sensor therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a frequently encountered clinical problem and associates with high mortality in a critical care setting. It is furthermore an important contributor to the progressionof chronic kidney disease (CKD). A central pathway in the regulation of renal hypoxia/ischemia responses is the prolyl-hydroxylase (PHD)/hypoxia-inducible factor (HIF) oxygen-sensing pathway. PHD proteins are iron- and 2-oxoglutarate-dependent oxygenases that function as oxygen sensors and regulate HIF activity by catalyzing the hydroxylation of specific proline residues within the oxygen-dependent degradation domain of it's alpha-subunit. HIFs are pleiotropic heterodimeric transcription factors that play key roles in cellular adaptation and survival under hypoxic/ischemic conditions. All three main HIF-PHDs, PHD1, -2 and -3, are expressed in the kidney. While PHD2 regulates HIF-1 activity in renal epithelial cells and has been shown to control erythropoietin production in renal interstitial cells, the role of PHD1 and PHD3 in renal hypoxia responses and pathophysiology is unknown. Our laboratory and other groups have demonstrated in preclinical animal models that short-term pharmacologic inactivation of renal PHDs has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. In order to understand the functional role of individual PHDs in renal physiology and to gain insight into the molecular and cellular basis of PHD/HIF-mediated renoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific PHD functions and their role in the regulation of renal metabolism. Here we hypothesize that PHD/HIF-controlled re-programming of metabolism in renal epithelial cells plays a central role in determining the biological outcome of ischemic kidney injuries. Under this grant we use genetically engineered mice to investigate the metabolic consequences of acute PHD inactivation in the kidney. Three specific aims are proposed. Aims 1 investigates the role of PHD2 in renal energy metabolism, aim 2 examines the functional role of tubular epithelial PHD1 and PHD3 in renal physiology and IRI, and aim 3 examines specific metabolic pathways that associate with cytoprotection in IRI.

描述（由申请人提供）：缺血 - 再灌注损伤（IRI）引起的急性肾脏损伤（AKI）是一个经常遇到的临床问题，并且在重症监护环境中具有高死亡率的伴侣。此外，这是导致慢性肾脏疾病（CKD）进展的重要原因。调节肾脏缺氧/缺血反应的中心途径是丙基羟化酶（PHD）/缺氧诱导因子（HIF）氧气感应途径。 PHD蛋白是铁和2-氧化羟基依赖性的氧酶，通过催化其Alpha-subunit的氧依赖性降解结构域内的特定脯氨酸残基的羟基化来调节HIF活性。 HIF是多效性异二聚体转录因子，在低氧/缺血性条件下在细胞适应和存活中起关键作用。所有三个主要的HIF -PHD PHD1，-2和-3均在肾脏中表达。虽然PHD2调节肾上皮细胞中的HIF-1活性，并且已显示可控制肾脏间质细胞中的红细胞生成素的产生，但PHD1和PHD3在肾脏缺氧反应中的作用和病理生理学在肾脏缺氧反应中的作用尚不清楚。我们的实验室和其他小组在临床前动物模型中证明了肾脏PHD的短期药物失活具有防止急性缺血性损伤及其长期后遗症的巨大治疗潜力。为了理解单个PHD在肾脏生理学中的功能作用，并深入了解了PHD/HIF介导的肾脏肾脏保护的分子和细胞基础，我们已经开始使用遗传和药理方法来剖析细胞类型特异性的PHD功能及其在肾脏代谢的调节中的作用。在这里，我们假设肾上皮细胞中代谢的博士/HIF控制重新编程在确定缺血性肾脏损伤的生物学结果方面起着核心作用。根据这笔赠款，我们使用基因工程小鼠研究肾脏急性博士学位的代谢后果。提出了三个具体目标。 AIMS 1研究了PHD2在肾脏能量代谢中的作用，AIM 2研究了管状上皮PHD1和PHD3在肾脏生理学和IRI中的功能作用，AIM 3检查了IRI中与细胞保护膜相关的特定代谢途径。