CD80 Expression on Podocytes and the Pathogenesis of Minimal Change Disease

足细胞CD80表达与微小病变病发病机制

• 批准号: 8334050
• 负责人: Eduardo Humberto Garin
• 金额: $ 17.97万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334050
• 关键词: Actins; Address; Adrenal Cortex Hormones; Adult; Animal Model; Area; Automobile Driving; Biopsy; CD80 gene; CTLA4-Ig; Cell Culture Techniques; Cells; Child; Childhood; Clinical; Clinical Research; Collaborations; DNA Sequence Rearrangement; Data; Development; Diagnostic tests; Disease; Disease remission; Etiology; Excretory function; Focal Segmental Glomerulosclerosis; Functional disorder; Human; Immune; In Vitro; Individual; Interferons; International; Kidney; Laboratory Study; Lead; Ligands; Mediating; Mononuclear Leukocytes; Morbidity - disease rate; Mus; Nephrology; Nephrotic Syndrome; Paper; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Permeability; Prevention; Proteins; Proteinuria; Publications; Publishing; Regulatory T-Lymphocyte; Relapse; Renal glomerular disease; Role; Serum; Shapes; Signal Pathway; Signal Transduction; Specificity; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; United States National Institutes of Health; Urine; base; disease diagnosis; in vitro Model; innovation; insight; interdisciplinary approach; novel diagnostics; peripheral blood; podocyte; professor; response; success; synaptopodin; treatment strategy; urinary

DESCRIPTION (provided by applicant): Minimal change disease (MCD) is the most common nephrotic syndrome in children, and can be associated with marked morbidity. Currently the etiology of MCD is unknown, but it has been hypothesized to be due to a circulating factor, possibly released by activated T cells, that induces podocyte dysfunction, resulting in an alteration of glomerular permeability with the development of nephrotic proteinuria. Our group has hypothesized that MCD is mediated by a phenotypic change in podocytes in which they express CD80, which is then shed into the urine as the podocyte undergoes shape change. In preliminary data we have found elevated levels of urinary CD80 in patients with active (relapsing) MCD and that it is absent in normal individuals, in MCD in remission, and in proteinuric subjects with focal segmental glomerulosclerosis. We have also identified CD80 in podocytes of limited numbers of renal biopsies of subjects with MCD. We have also developed an in vitro model of MCD in which we can activate toll-like receptors present on cultured human podocytes and show that it activates interferon and NF:B dependent pathways with the expression of CD80, shape change (actin rearrangement) and loss of synaptopodin, and we can rescue this with corticosteroids (which are used clinically to treat minimal change disease). In this application we will first perform cell culture studies to evaluate the potential role of serum and peripheral blood mononuclear leukocyte supernatants from subjects with and without MCD in stimulating CD80 expression in vitro, to determine the cellular signaling pathways by which Toll-like receptor ligands stimulate CD80 in podocytes in vitro, and to develop an animal model of MCD based on these findings. Second, we will perform additional clinical studies to determine the specificity, temporal excretion and podocyte expression of CD80 in MCD compared to other glomerular disorders. We will also examine the urinary excretion and podocyte expression of CTLA-4 for which we hypothesize is the factor that autoregulates the CD80 response. It is our hope that these studies may elucidate not only the cause of minimal change disease but also reveal new strategies for treatment and prevention.

描述（由申请人提供）：最小变化病（MCD）是儿童中最常见的肾病综合征，可与显著的发病率相关。目前MCD的病因尚不清楚，但据推测是由于一种循环因子，可能由活化的T细胞释放，诱导足细胞功能障碍，导致肾小球通透性随着肾病性蛋白尿的发展而改变。我们的研究小组假设MCD是由足细胞的表型变化介导的，其中它们表达CD80，然后随着足细胞发生形状变化而进入尿液。在初步数据中，我们发现活动性（复发性）MCD患者尿CD80水平升高，而在正常个体、MCD缓解期和蛋白尿伴局灶节段性肾小球硬化患者中则不存在。我们也在MCD患者的少量肾活检的足细胞中发现了CD80。我们还开发了MCD的体外模型，在该模型中，我们可以激活存在于培养的人足细胞上的toll样受体，并表明它可以激活干扰素和NF:B依赖通路，表达CD80，形状改变（肌动蛋白重排）和突触肽的丢失，并且我们可以用皮质类固醇（临床上用于治疗微小变化疾病）来挽救这种情况。在这项应用中，我们将首先进行细胞培养研究，以评估患有和不患有MCD的受试者的血清和外周血单核白细胞上清液在体外刺激CD80表达中的潜在作用，确定toll样受体配体在体外刺激足细胞CD80的细胞信号通路，并基于这些发现建立MCD的动物模型。其次，我们将进行额外的临床研究，以确定CD80在MCD中的特异性、时间排泄和足细胞表达与其他肾小球疾病的比较。我们还将检查尿排泄和足细胞CTLA-4的表达，我们假设CTLA-4是自动调节CD80反应的因素。我们希望这些研究不仅可以阐明微小变化疾病的原因，还可以揭示治疗和预防的新策略。