The Role of Bone Marrow Derived Eicosanoids in Renal Disease Progression

骨髓衍生的类二十烷酸在肾脏疾病进展中的作用

• 批准号: 10454218
• 负责人: John Ross Montford
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454218
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Allergic Reaction; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonate 15-Lipoxygenase; Atherosclerosis; Autacoids; Autoimmune; Automobile Driving; Back; Biology; Bone Marrow; Bone Marrow Involvement; Bone Marrow Transplantation; Cell Culture Techniques; Cell Differentiation process; Cells; Chemical Agents; Chronic; Chronic Kidney Failure; Collection; Data; Diabetes Mellitus; Dinoprostone; Disease; Disease Progression; Docosahexaenoic Acids; Eicosanoids; Enzymes; Epithelial Cells; Equilibrium; Fibrosis; Flow Cytometry; Folic Acid; Future; Gene Expression Profiling; General Population; Genetic; Goals; Health system; Histologic; Human; Hydroxyeicosatetraenoic Acids; Imaging technology; Immune; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knowledge; Leukocytes; Light; Link; Lipids; Mediating; Mediator of activation protein; Microscopic; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; PPAR gamma; Pathogenesis; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacology; Pharmacotherapy; Phenotype; Phospholipid Metabolism; Play; Production; Prostaglandin-Endoperoxide Synthase; Proteinuria; Publishing; Receptor Signaling; Regulation; Renal Tissue; Renal function; Role; Series; Solid; Standardization; Stimulus; Stress; Techniques; Testing; Translating; Transplantation; Tubular formation; Ureteral obstruction; Veterans; Veterans Health Administration; cell injury; cell type; cytokine; epithelial injury; experimental study; global health; in vitro Model; in vivo; inhibitor; interest; kidney fibrosis; lipidomics; macrophage; monocyte; mortality; mouse PGE synthase 1; novel; novel therapeutic intervention; novel therapeutics; receptor; recruit; renal damage; renal epithelium; response; therapy development; tissue injury; tool

Eicosanoids are biologically active products of phospholipid metabolism which are involved in the pathogenesis of numerous autoimmune and inflammatory diseases in humans. Published data has implicated that eicosanoids derived from the microsomal Prostaglandin Synthase type 1 (mPGES-1) and 15-Lipoxygenase (12/15-LOX) enzymes are involved in mediating tissue injury in multiple different cell types including epithelial cells and bone marrow derived monocytes (BMDMs). Of note, mPGES-1 and 12/15-LOX are thought to be critical mediators of kidney damage in many different animal models of acute and chronic renal diseases. In order to develop novel therapeutic approaches to treat kidney disease, in particular chronic kidney disease (CKD), a better understanding of how eicosanoids are produced among specific cell types in the disease renal microenvironment is urgently needed. Our overall hypothesis is that mPGES-1 and 12/15-LOX-derived products from both resident cells and recruited inflammatory cells are instrumental in pathways that control renal epithelial injury, inflammation, and fibrosis during UUO; and that manipulating the balance of these eicosanoids by genetic or pharmacologic means is a viable therapy to modify renal disease progressions This proposal seeks to test this hypothesis using a bone marrow transplantation approach to generate mice chimeric for mPGES-1 and 12/15-LOX expression. These mice will undergo unilateral ureteral obstruction (UUO), a model of renal fibrosis; and chronic folic acid nephropathy, a model of fibrosis and CKD progression. Renal tissue injury and renal failure will be quantified using standardized as well as cutting edge techniques. We will employ state of the art microscopy, flow cytometry, transcriptional profiling, and lipidomic analysis in our studies. We will compare how targeted deletion of mPGES-1 and 12/15-LOX from infiltrating bone marrow-derived cells and from resident cell types influence renal injury and CKD progression. Additionally, we will study the effects of these two pathways in a novel cell culture in-vitro model using monocytes and renal epithelial cells isolated directly from genetically altered mice. We will examine how cell- specific expression of these enzymes and products in monocytes and epithelial cells influences downstream molecular pathways which will be further altered using experimental chemical agents. These studies will provide solid mechanistic evidence for novel therapeutic approaches to treat humans with kidney disease.

类二十烷酸是磷脂代谢的生物活性产物