FOCAL SEGMENTAL GLOMERULOSCLEROSIS--PATHOGENESIS AND TREATMENT

局灶节段性肾小球硬化——发病机制和治疗

• 批准号: 6289795
• 负责人: Jeffrey B Kopp
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289795
• 关键词: ACE inhibitors; African American; HIV infections; clinical research; disease /disorder model; family genetics; genetically modified animals; glomerulosclerosis; human subject; laboratory mouse; linkage disequilibriums; molecular pathology; virus genetics

We wish to characterize the mechanisms for responsible for focal segmental glomerulosclerosis (FSGS) and use these findings to devise more effective therapy; we are particularly interested in HIV- associated FSGS.We have hypothesized that HIV accessory proteins (Vpr, Vpu, and Vif) mediate renal injury, leading to the histologic pattern of focal segmental glomerulosclerosis. We have established transgenic lines which will express Vpr under the control of a tetracycline inducible promoter.We have collected blood and prepared immortalized B cell lines as a source of DNA from approximately 160 African-American patients with FSGS and a control group 210 African Americans infected with HIV but without renal disease, with the help of collaborators from 12 medical centers around the country. We have initiated candidate gene analysis and plan a genome scan within the next year.We have submitted a protocol to test two agents, pirfenidone and probucol, in 20 patients with idiopathic or HIV-associated FSGS using a randomized block design, with each drug used as a single agent for 4 months and with proteinuria as the primary endp - focal segmental glomerulosclerosis, kidney disease, African American, HIV-1, Vpu, Vpr, Vif - Human Subjects

我们希望表征负责局灶性节段性肾小球硬化（FSG）的机制，并使用这些发现来设计更有效的治疗；我们对与HIV相关的FSG特别感兴趣。我们假设HIV辅助蛋白（VPR，VPU和VIF）介导肾损伤，从而导致局灶性节段性肾小球硬化的组织学模式。我们已经建立了转基因线，该线将在四环素可诱导的启动子的控制下表达VPR。我们收集了血液，并准备好了永生的B细胞系，作为来自大约160名FSGS的160名非裔美国人患者的DNA来源，并与对照组的210组210名非裔美国人感染了艾滋病毒，但没有肾脏疾病，但没有与12个医学中心的肾脏疾病，围绕着12个医学中心。我们已经启动了候选基因分析，并计划了明年的基因组扫描。我们提交了一项协议，用于测试两种药物，pirfenidone和progucol，其中20例具有特发性或HIV相关的FSG的患者使用随机块设计，每种药物用作单一药物，并用单个药物使用4个月，并与蛋白质的蛋白酶蛋白酶播出了4个月 - HIV -1，VPU，VPR，VIF-人类受试者