Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

描述(由申请人提供)：越来越多的证据表明足细胞在各种肾小球疾病的发生和发展中起着关键作用。我们发现，在病理条件下，随着足突消失和蛋白尿，足细胞表达分子B7-1(也称为CD80)，这是一种表达在B细胞和抗原提呈细胞(APC)表面的跨膜蛋白。在B细胞和APC上，B7-1通过与其受体CD28和CTLA-4结合，为T细胞提供共刺激信号。B7-1的免疫功能已经得到了很好的描述。关于B7-1在非骨髓来源细胞中的表达和功能，人们知之甚少。在这里，我们提供了B7-1在足细胞中扮演新角色的证据。我们的初步数据表明，足细胞中B7-1的上调通过改变肾小球通透性而参与了蛋白尿的发病机制，并为治疗蛋白尿性肾病提供了一个新的分子靶点。基于我们的观察，我们提出了一个新的工作模型/假说：足细胞表达B7-1代表了肾小球滤过装置破坏的致病机制。B7-1可能以双重方式参与蛋白尿的发病机制：i)通过诱导足突消失和隔离重要的SD分子远离其正常作用部位，从而改变肾小球通透性；ii)通过调节足细胞-基质黏附。我们提出了三个特定的目标来验证我们的中心假设：特定目标1将阐明B7-1协调足细胞肌动蛋白细胞骨架和SD复合体重组的机制。具体目标2将探讨B7-1在足细胞与细胞外基质黏附中的作用。特异的Aim3将证实B7-1在足细胞中的表达在蛋白尿性肾小球疾病的发病机制中的作用。如果我们的假设是正确的，本文提出的工作将在长期内具有广泛的意义，因为它将建立对B7-1、足突消失、肌动蛋白细胞骨架和肾病综合征/FSGS中SD复合体之间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的进展。

DESCRIPTION (provided by applicant): Increasing evidence points to a critical role of podocytes in the initiation and progression of various glomerular diseases. We made the unexpected finding that under pathological conditions, with foot process effacement and proteinuria, podocytes express the molecule B7-1 (also termed CD80), a transmembrane protein expressed on the surface of B-cells and antigen presenting cells (APC). On B-cells and APC, B7-1 provides a costimulatory signal for T-cells through binding to its receptors CD28 and CTLA-4. The immune function of B7-1 has been well described. Much less is known about B7-1 expression and function in non-bone marrow derived cells. Here we provide evidence for a novel role of B7-1 in podocytes. Our preliminary data suggest that up regulation of B7-1 in podocytes contributes to the pathogenesis of proteinuria by altering glomerular permselectivity and provide a novel molecular target to tackle proteinuric kidney disease. Based on our observations, we propose a new working model/hypothesis: B7-1 expression by podocytes represents a pathogenic mechanism for disruption of the glomerular filtration apparatus. B7-1 may contribute to the pathogenesis of proteinuria in a dual fashion: i) by induction of foot process effacement and sequestration of vital SD molecules away from their normal sites of action, thereby altering glomerular permselectivity and ii) by modulating podocyte-matrix adhesion. We propose three Specific Aims to test our central hypothesis: Specific Aim 1 will elucidate the mechanism by which B7-1 orchestrates the reorganization of the podocyte actin cytoskeleton and SD complex. Specific Aim 2 will explore the role of B7-1 in podocyte adhesion to extracellular matrix. Specific Aim3 will establish the contribution of B7-1 expression in podocytes to the pathogenesis of proteinuric glomerular 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, foot process effacement, the actin cytoskeleton and the SD complex in nephrotic syndrome/FSGS. 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.