CD80 Expression on Podocytes and the Pathogenesis of Minimal Change Disease

描述（由申请人提供）：微小病变（MCD）是儿童最常见的肾病综合征，并可能与显著的发病率相关。目前，MCD的病因尚不清楚，但已假设是由于循环因子，可能由活化的T细胞释放，诱导足细胞功能障碍，导致肾小球通透性改变，发生肾病蛋白尿。我们的小组假设MCD是由足细胞的表型变化介导的，足细胞表达CD 80，然后随着足细胞的形状变化而脱落到尿液中。在初步数据中，我们发现活动性（复发性）MCD患者的尿CD 80水平升高，而正常人、缓解期MCD患者和局灶节段性肾小球硬化蛋白尿患者均不存在。我们还在MCD受试者有限数量的肾活检的足细胞中鉴定了CD 80。我们还开发了一种MCD体外模型，在该模型中，我们可以激活培养的人足细胞上存在的Toll样受体，并显示其激活干扰素和NF：B依赖性途径，表达CD 80、形状改变（肌动蛋白重排）和突触足蛋白丢失，我们可以用皮质类固醇（临床上用于治疗微小病变疾病）挽救这种情况。在本申请中，我们将首先进行细胞培养研究，以评价患有和不患有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CD 80表达中的潜在作用，以确定Toll样受体配体体外刺激足细胞中CD 80的细胞信号传导途径，并基于这些发现开发MCD动物模型。其次，我们将进行额外的临床研究，以确定与其他肾小球疾病相比，MCD中CD 80的特异性、时间排泄和足细胞表达。我们还将检查尿排泄和足细胞表达的CTLA-4，我们假设是因子，自动调节CD 80的反应。我们希望这些研究不仅可以阐明微小病变疾病的原因，而且还可以揭示治疗和预防的新策略。 公共卫生相关性：微小病变是儿童肾病综合征的最常见原因，并导致广泛的发病率。该提案中概述的研究旨在确定驱动这种疾病的潜在机制，并确定是否可以开发更好的非侵入性方法来诊断这种疾病。这些研究不仅可以深入了解这种疾病的原因，还可以提供新的治疗目标和策略。

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. PUBLIC HEALTH RELEVANCE: Minimal change disease is the most common causes of nephrotic syndrome in children and causes extensive morbidity. The studies outlined in this proposal are aimed at identifying both the underlying mechanism driving this disease and also determining if one can develop a better and noninvasive means for diagnosing this disease. These studies will not only provide insights into the cause of this condition, but may also provide new targets and strategies for treatment.