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：
8092815
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/8092815
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 Health 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

DESCRIPTION (provided by applicant): Collapsing glomerulopathy (CG) is a common but poorly understood proliferative podocytopathies 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-a 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. PUBLIC HEALTH RELEVANCE: Collapsing glomerulopathy has emerged as an important cause of renal failure within the past three decades. The reasons for why patients can be afflicted with collapsing glomerulopathy are poorly understood, and, as a result, there are currently no effective therapies for this devastating renal disease. This R01 proposal seeks to better understand how activation of the immune system contributes to the development and progression of collapsing glomerulopathy and to design new therapeutic strategies based on this knowledge.

描述（由申请人提供）：崩溃的肾小球病（CG）是一种常见但知之甚少的增生性足细胞病，可以预测快速的肾功能衰竭和对经验疗法的难治性。临床相关性表明，CG是由顽固性宿主敏感性和促炎性免疫介质的致病相互作用引起的。在此提案中，我们试图阐明如何丢失足细胞的免疫细胞保护剂，并且在容易受到CG敏感的宿主中可以恢复。为此，我们已经将TNF-A与Podocytes上TNF受体2（TNFR2）的相互作用确定为CG的潜在沉淀物。反过来，由于足细胞对炎症介质没有已知的耐受性，因此我们绘制了肾脏树突状细胞（DC）网络以通过调节性DC询问Podocyte的保护。我们的临床前测试证明了细胞周期蛋白依赖性激酶/糖原合酶激酶3抑制剂（CGIS）的预防和CG逆转，这些抑制剂（CGIS）是广泛适用的新肾脏疗法，这些新肾脏疗法被发现诱导有效的，免疫细胞的调节性调节性DC。因此，我们在这里假设调节性DC可防止TNFR2介导的CG沉淀，CG（CGIS的治疗作用），在以下三个具体目的中：1）确定易受CG的TNFR2 NULL小鼠中的Podocyte保护； 2）在TNFR2竞争CG的TNFR2中确定调节DC的足细胞保护； 3）通过INDIRUBIN CGIS验证CG中的药理学免疫细胞保护。这些研究将描述导致CG降水和保护的免疫机制，并确定这种毁灭性肾脏疾病的新干预措施。公共卫生相关性：在过去的三十年中，肾小球病崩溃已成为肾衰竭的重要原因。人们对肾小球病的折磨的原因很少了解，因此，目前尚无对这种毁灭性肾脏疾病的有效疗法。该R01提案旨在更好地理解免疫系统的激活如何有助于崩溃的肾小球病的发展和发展，并根据这些知识设计新的治疗策略。