EICOSANOIDS IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS

类花生酸在局灶性节段性肾小球硬化中的作用

• 批准号: 2677006
• 负责人: ELLEN T MCCARTHY
• 金额: $ 10.79万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-25 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2677006
• 关键词: eicosanoids; enzyme activity; fatty acid biosynthesis; gene expression; glomerulosclerosis; laboratory rat; membrane permeability; phospholipase A2; prostaglandin endoperoxide synthase; renal glomerulus; serum albumin; tissue /cell culture

DESCRIPTION (adapted from the application) Focal segmental glomerulosclerosis (FSGS) is a renal disease of unknown etiology characterized by heavy proteinuria, hypertension, and progression to renal failure. The incidence of FSGS has increased by up to 8-fold in the past 20 years. It is the now the most common progressive glomerular disease in children and account for 20_25% of nephrotic syndrome in adults. Cyclooxygenase (COX) inhibitors decrease proteinuria in many proteinuric glomerular disease, including FSGS. The applicant has participated in studies that document the presence of a plasma factor in patients with FSGS which causes an increase in glomerular albumin permeability. In preliminary studies, she has shown that the COX inhibitor indomethacin prevented the increased in albumin permeability caused by the FSGS factor, thus implicating eicosanoids of the COX pathways of arachidonic acid metabolism as mediators of this effect. In the proposed studies, she will determine the role of these eicosanoids in mediating the increased glomerular protein permeability caused by the FSGS factor, and explore mechanisms by which this factor regulated synthesis of COX-derived eicosanoids. Hypothesis to be tested are: (1) the FSGS factor increased synthesis of specific eicosanoids of the COX pathway, and these eicosanoids increase glomerular albumin permeability; (2) the FSGS factor increases synthesis of COX-derived eicosanoids via an effect on activity and/or expression of phospholipase A2 (PLA2), constitutive COX or inducible COX. She will measure eicosanoid production by isolated glomeruli or cultured glomerular cells after incubation with the FSGS factor and will then determine the effect of eicosanoids identified in these studies, on glomerular albumin permeability. Finally, she will investigate the mechanism by which the FSGS factor enhance eicosanoid synthesis by measuring activity and expression (mRNA and protein) of PLA, and of constitutive and inducible COX in glomeruli and in cultured glomerular cells. The proposed project is expected to provide the applicant with valuable opportunities to expand hew knowledge and expertise in experimental design, investigative techniques, and data analysis. Results of these studies will provide insight into the pathophysiology of FSGS. Additionally, they may lead to a better understanding of the general mechanism by which proteinuria develops and thus point to interventions that may alleviate or prevent proteinuria in FSGS and in other glomerular diseases.

描述（改编自应用程序） 局灶节段性肾小球硬化症 (FSGS) 是一种未知的肾脏疾病 病因以大量蛋白尿、高血压和进展为特征 至肾功能衰竭。 FSGS 的发病率增加了 8 倍 过去20年。它是目前最常见的进行性肾小球 儿童肾病综合征占20-25% 成年人。环加氧酶 (COX) 抑制剂可减少许多人的蛋白尿 蛋白尿性肾小球疾病，包括 FSGS。申请人有 参与了记录血浆因子存在的研究 导致肾小球白蛋白增加的 FSGS 患者 渗透性。在初步研究中，她表明 COX 抑制剂 吲哚美辛可防止白蛋白通透性增加 FSGS 因子，因此暗示了 COX 途径中的类二十烷酸 花生四烯酸代谢作为这种效应的介质。在提议的 研究中，她将确定这些类二十烷酸在调节 FSGS 因子引起的肾小球蛋白通透性增加，以及 探索该因子调节 COX 衍生的合成的机制 类二十烷酸。待检验的假设为： (1) FSGS 因子增加 COX 途径的特定类二十烷酸的合成，以及这些 类二十烷酸增加肾小球白蛋白通透性； (2) FSGS因子 通过影响活性来增加 COX 衍生的类二十烷酸的合成 和/或磷脂酶A2 (PLA2)、组成型COX或的表达 诱导型COX。她将通过分离的方法来测量类二十烷酸的产生 与 FSGS 一起孵育后的肾小球或培养的肾小球细胞 因素，然后确定类花生酸的作用 这些研究是关于肾小球白蛋白通透性的。最后，她会 研究 FSGS 因子增强类二十烷酸的机制 通过测量 PLA 的活性和表达（mRNA 和蛋白质）来合成， 以及肾小球和培养物中的组成型和诱导型 COX 肾小球细胞。拟议项目预计将提供 申请人有宝贵的机会来扩展知识和 实验设计、研究技术和数据方面的专业知识 分析。这些研究的结果将提供对 FSGS 的病理生理学。此外，它们可能会带来更好的结果 了解蛋白尿发生的一般机制 因此指出可以减轻或预防蛋白尿的干预措施 FSGS 和其他肾小球疾病。