EICOSANOIDS IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS

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， 病因学特征为大量蛋白尿、高血压和进展 到肾衰竭FSGS的发病率在2008年增加了8倍。 过去20年它是目前最常见的进行性肾小球疾病 占肾病综合征的20%~ 25 成年人了环氧合酶（考克斯）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。申请人已经 参与了一些研究，这些研究记录了 导致肾小球白蛋白升高的FSGS患者 磁导率在初步的研究中，她已经表明，考克斯抑制剂 吲哚美辛阻止了由白蛋白通透性增加引起的白蛋白通透性增加， FSGS因子，从而暗示类花生酸的考克斯途径， 花生四烯酸代谢作为这种作用的介质。拟议 研究，她将确定这些类花生酸在介导 由FSGS因子引起的肾小球蛋白渗透性增加，和 探索该因子调节COX衍生的合成的机制 类花生酸待检验的假设为：（1）FSGS因子增加 合成考克斯途径的特异性类花生酸，这些 类花生酸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衍生类二十烷酸的合成 和/或磷脂酶A2（PLA 2）、组成型考克斯或 诱导型考克斯。她将测量类花生酸的产生， 与FSGS孵育后的肾小球或培养的肾小球细胞 因素，然后将确定中确定的类二十烷酸的影响， 这些关于肾小球白蛋白渗透性的研究。最后，她会 研究FSGS因子增强类花生酸的机制 通过测量PLA的活性和表达（mRNA和蛋白质）合成， 以及肾小球和培养的肾小球中组成型和诱导型考克斯的表达。 肾小球细胞预计拟议项目将提供 申请人有宝贵的机会，以扩大新的知识和 实验设计、调查技术和数据方面的专业知识 分析.这些研究的结果将提供深入了解 FSGS的病理生理学此外，它们可能会导致更好的 了解蛋白尿发生的一般机制， 因此指出，干预措施，可以减轻或预防蛋白尿， 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.