Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

描述(申请人提供)：B7-1(CD80)是一种B细胞和其他抗原提呈细胞的跨膜蛋白，最初被鉴定为通过CD28或CTLA-4与T细胞结合来调节T细胞的激活和耐受。我们先前报道，在FP消退和蛋白尿的病理条件下，肾脏足细胞表达B7-1。足细胞B7-1的表达与人类狼疮性肾炎的严重程度相关，这些结果的临床意义得到了强调。我们建议验证我们的中心假设，即足细胞中的B7-1通过改变足细胞肌动蛋白动力学、足细胞与基底膜的黏附以及裂隙横隔膜的结构和功能而参与蛋白尿的发病机制。为了验证这一假设，我们提出了以下三个具体目标。第一个目标将确定B7-1协调足细胞肌动蛋白细胞骨架重组的分子机制。具体目的二是探讨B7-1在足细胞与细胞外基质黏附中的作用。第三个目的将确定足细胞B7-1的表达在蛋白尿性肾脏疾病的发病和进展中的作用。如果我们的假设是正确的，从长远来看，这里提出的工作将具有广泛的意义，因为它将建立对B7-1、足细胞肌动蛋白细胞骨架和SD复合体在蛋白尿性肾脏疾病中相互作用的动力学的洞察。从长远来看，这将使我们能够开发新的、选择性的足细胞保护性疗法，通过阻断足细胞中B7-1的活性来治疗蛋白尿和肾小球硬化。公共卫生相关性：这里提出的工作应该为足细胞表达B7-1导致蛋白尿的分子机制提供洞察力。从长远来看，这将使我们能够开发新的、选择性的足细胞保护性疗法，通过阻断足细胞中B7-1的活性来治疗蛋白尿和肾小球硬化的进展。

DESCRIPTION (provided by applicant): B7-1 (CD80) is a transmembrane protein of B cells and other antigen presenting cells, which was originally identified as a regulator of T cell activation and tolerance through CD28 or CTLA-4 binding on T cells. We previously reported that under pathological conditions with FP effacement and proteinuria, kidney podocyte express B7-1. The clinical significance of these results was underscored by the observation that podocyte B7-1 expression correlates with the severity of human lupus nephritis Here we propose to test our central hypothesis that B7-1 in podocytes contributes to the pathogenesis of proteinuria by altering podocyte actin dynamics, podocyte adhesion to the GBM, and slit diaphragm structure and function. To test this hypothesis we propose the following three Specific Aims. The first Aim will define the molecular mechanism whereby B7-1 orchestrates the reorganization of the podocyte actin cytoskeleton. Specific Aim two seeks to explore the role of B7-1 in podocyte adhesion to extracellular matrix. The third Aim will determine the contribution of podocyte B7-1 expression to the pathogenesis and progression of proteinuric kidney diseases. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of the interaction between B7-1, the podocyte actin cytoskeleton and the SD complex in proteinuric kidney diseases. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and glomerulosclerosis by blocking the activity of B7-1 in podocytes. PUBLIC HEALTH RELEVANCE: The work proposed here should provide insight into the molecular mechanism whereby B7-1 expression in podocytes causes proteinuria. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and progression of glomerulosclerosis by blocking the activity of B7-1 in podocytes.