The Role of Bone Marrow Derived Eicosanoids in Renal Disease Progression

二十烷基类化合物是磷脂代谢的生物活性产物，参与了 人类多种自身免疫性和炎症性疾病的发病机制。公布的数据表明 二十烷基类化合物来源于微粒体前列腺素合成酶1型(mPGES-1)和15-脂氧合酶 (12/15-LOX)酶参与多种不同细胞类型的组织损伤，包括上皮细胞 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动物模型中肾脏损伤的关键介质。 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)，更好地了解疾病中特定细胞类型中二十烷类化合物是如何产生的 迫切需要肾脏微环境。我们的总体假设是mPGES-1和12/15-LOX衍生 来自驻留细胞和招募的炎症细胞的产物在控制 UUO过程中的肾上皮损伤、炎症和纤维化；以及对这些平衡的调控 二十烷酸类化合物通过遗传或药物手段是一种可行的延缓肾脏疾病进展的治疗方法。 这项提议试图使用骨髓移植方法来检验这一假设，以产生 小鼠嵌合表达mPGES-1和12/15-LOX。这些小鼠将接受单侧输尿管 梗阻(UUO)，肾脏纤维化的模型；慢性叶酸肾病，纤维化和CKD的模型 进步。肾组织损伤和肾功能衰竭将使用标准化和尖端技术进行量化 技巧。我们将使用最先进的显微镜、流式细胞术、转录图谱和脂组学技术。 在我们的研究中进行分析。我们将比较mPGES-1和12/15-LOX的靶向缺失如何从渗透中 骨髓来源的细胞和常驻细胞类型会影响肾脏损伤和CKD的进展。 此外，我们还将在一种新的体外细胞培养模型中研究这两种途径的作用。 直接从转基因小鼠分离的单核细胞和肾上皮细胞。我们将研究细胞如何- 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 将使用实验化学试剂进一步改变的分子途径。这些研究将 为治疗人类肾脏疾病的新治疗方法提供坚实的机械证据。

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.