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: 9898241
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898241
• 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 Process; Automobile Driving; Back; Biological; 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; Expression Profiling; 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; cell injury; cell type; cytokine; epithelial injury; experimental study; global health; health administration; in vitro Model; in vivo; inhibitor/antagonist; interest; kidney fibrosis; 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，其参与磷脂代谢。 在人类的许多自身免疫性和炎性疾病的发病机制。公布的数据表明， 类花生酸来源于微粒体前列腺素合酶1（mPGES-1）和15-脂氧合酶 (12 15-LOX）酶参与介导多种不同细胞类型（包括上皮细胞）中的组织损伤 细胞和骨髓来源的单核细胞（BMDM）。值得注意的是，mPGES-1和12/15-LOX被认为是 在许多不同的急性和慢性肾脏疾病的动物模型中，肾损伤的关键介质。 为了开发新的治疗方法来治疗肾脏疾病，特别是慢性肾脏疾病， 疾病（CKD），更好地了解如何在疾病中的特定细胞类型中产生类花生酸 肾脏微环境的改善是迫切需要的。我们的总体假设是mPGES-1和12/15-LOX衍生的 来自驻留细胞和募集的炎症细胞的产物在控制炎症的途径中起作用， UUO期间肾上皮损伤，炎症和纤维化;以及操纵这些平衡 通过遗传学或药理学手段的类花生酸是一种改变肾脏疾病进展的可行疗法 该提案试图使用骨髓移植方法来测试这一假设， mPGES-1和12/15-LOX表达的嵌合小鼠。这些小鼠将接受单侧输尿管 梗阻（UUO），肾纤维化模型;和慢性叶酸肾病，纤维化和CKD模型 进展肾组织损伤和肾衰竭将使用标准化和最新的 技术.我们将采用最先进的显微镜，流式细胞术，转录谱，脂质组学， 在我们的研究中分析。我们将比较mPGES-1和12/15-LOX的靶向缺失如何从浸润性细胞中诱导表达。 骨髓来源的细胞和来自驻留细胞类型的细胞影响肾损伤和CKD进展。 此外，我们将研究这两种途径在一种新的细胞培养体外模型中的作用， 单核细胞和肾上皮细胞直接分离自遗传改变的小鼠。我们将研究细胞- 这些酶和产物在单核细胞和上皮细胞中的特异性表达影响下游 分子途径，这些分子途径将使用实验性化学试剂进一步改变。这些研究将 为治疗人类肾脏疾病的新治疗方法提供了可靠的机制证据。