EICOSANOIDS IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS

说明(改编自应用程序) 局灶性节段性肾小球硬化(FSGS)是一种未知的肾脏疾病 以大量蛋白尿、高血压和病情进展为特征的病因学 肾功能衰竭。FSGS的发病率在#年增加了8倍 在过去的20年里。它是目前最常见的进展性肾小球 儿童疾病，占#年肾病综合征的20-25% 成年人。环氧合酶(COX)抑制剂可减少许多患者的蛋白尿 蛋白尿性肾小球疾病，包括FSGS。申请人有 参与了一项研究，记录了血浆因子在 导致肾小球白蛋白升高的FSGS患者 渗透性。在初步研究中，她已经证明了COX抑制剂 吲哚美辛可预防由消炎痛引起的蛋白通透性增加 FSGS因子，从而牵涉到COX途径的二十烷基类化合物 花生四烯酸代谢作为这一效应的中介。在建议的 通过研究，她将确定这些二十烷类化合物在调节 FSGS因子引起的肾小球蛋白通透性增加，以及 探讨该因子调节COX-衍生产物合成的机制 二十烷类化合物。需要检验的假设是：(1)FSGS因子增加 COX途径的特定二十烷类化合物的合成，以及这些 二十碳二烯增加肾小球白蛋白通透性；(2)FSGS因子 通过对活性的影响增加COX衍生二十烷类化合物的合成 和/或磷脂酶A2(PLA2)、结构性COX或 诱导型考克斯。她将通过分离的方法来测量二十烷类化合物的产量 与FSGS孵育后的肾小球或培养的肾小球细胞 因素，然后将确定的二十烷类化合物的影响 这些研究，对肾小球白蛋白通透性的影响。最后，她会 探讨FSGS因子增强二十烷类化合物的机制 通过测定聚乳酸的活性和表达(mRNA和蛋白质)来合成， 在肾小球和培养的肾小球中结构性和诱导性COX的表达 肾小球细胞。拟议的项目预计将提供 应聘者有宝贵的机会扩大新知识和 在实验设计、调查技术和数据方面的专业知识 分析。这些研究的结果将为我们提供对 FSGS的病理生理学。此外，它们可能会带来更好的 了解蛋白尿发生和发展的一般机制 因此指出可以缓解或预防蛋白尿的干预措施 FSGS和其他肾小球疾病。

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.