Immunocytoprotection in collapsing glomerulopathy

塌陷性肾小球病中的免疫细胞保护

基本信息

批准号：
8287136
负责人：
PETER JACOB NELSON
金额：
$ 26.76万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-03 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8287136
关键词：
Ablation Adoptive Transfer Anti-Inflammatory Agents Anti-inflammatory Biological Response Modifiers Clinical Cyclin-Dependent Kinases Dendritic Cells Development Diagnosis Diphtheria Toxin Disease remission Drug effect disorder Failure Glycogen Synthase Kinase 3 Goals HIV Immune Immune system Inflammation Mediators Inflammatory Injury Intervention Kidney Kidney Diseases Kidney Failure Knockout Mice Knowledge Maps Mediating Modeling Mus Outcome Pathogenesis Patients Precipitation Predisposition Prevention Regimen Renal function Research Research Personnel TNF gene Therapeutic Therapeutic Effect Therapeutic Intervention Transgenes Transgenic Organisms Tumor Necrosis Factor Receptor Water base design effective therapy in vivo indirubin inhibitor/antagonist new therapeutic target novel therapeutic intervention novel therapeutics podocyte prevent programs prophylactic research clinical testing

项目摘要

PROJECT SUMMARY Collapsing glomerulopathy (CG) is a common but poorly understood proliferative podocytopathy that portends rapid renal failure and refractoriness to empiric therapy. Clinical correlates suggest that CG results from the pathogenic interaction of intractable host susceptibilities and pro-inflammatory immune mediators. In this proposal, we seek to elucidate how immunocytoprotection of podocytes is lost and may be restored in hosts susceptible to CG. Towards this end, we have identified the interaction of TNF-¿ with TNF receptor 2 (TNFR2) on podocytes as a potential precipitant of CG. In turn, because podocytes harbor no known tolerance to inflammatory mediators, we have mapped the renal dendritic cell (DC) network to interrogate podocyte protection by regulatory DCs. Our pre-clinical testing demonstrated prevention and reversal of CG by cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors (CGIs), broadly applicable new renal therapeutics discovered to induce potent, immunocytoprotective regulatory DCs. We therefore hypothesize here that regulatory DCs prevent TNFR2-mediated precipitation of CG, a therapeutic effect of CGIs, in the following three specific aims: 1) determine podocyte protection in TNFR2 null mice susceptible to CG; 2) determine podocyte protection by regulatory DCs in TNFR2 competent mice susceptible to CG; and 3) validate pharmacologic immunocytoprotection in CG via indirubin CGIs. These studies will delineate immune mechanisms leading to the precipitation of and protection from CG, and identify new interventions for this devastating renal disease.

项目概要塌陷性肾小球病（CG）是一种常见但人们知之甚少的增殖性足细胞病，预示着快速肾衰竭和经验性治疗无效。临床相关性表明 CG。顽固宿主易感性和促炎性免疫系统致病相互作用的结果在本提案中，我们试图阐明足细胞的免疫细胞保护是如何丢失和的。可能会在易受CG影响的宿主中恢复。为此，我们已经确定了相互作用。肿瘤坏死因子-¿足细胞上的 TNF 受体 2 (TNFR2) 作为 CG 的潜在沉淀剂。足细胞对炎症介质没有已知的耐受性，我们已经绘制了肾树突状图细胞 (DC) 网络来询问监管 DC 的足细胞保护作用。通过细胞周期蛋白依赖性激酶/糖原合酶激酶 3 预防和逆转 CG 抑制剂（CGI），广泛适用的新肾脏治疗药物，被发现可诱导有效的、因此，我们在此保留调节性树突状细胞可预防免疫细胞保护性调节性树突状细胞。 TNFR2介导的CG沉淀，CGIs的治疗作用，有以下三个具体目的： 1) 确定对 CG 敏感的 TNFR2 缺失小鼠的足细胞保护；2) 确定足细胞；调节性 DC 对 CG 敏感的 TNFR2 小鼠的保护作用；以及 3) 验证；通过靛红 CGI 进行 CG 的药理免疫细胞保护这些研究将描述免疫。导致 CG 沉淀和保护的机制，并确定新的干预措施这种毁灭性的肾脏疾病。