Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

描述(申请人提供)：B7-1/CD80是已知的T细胞激活和耐受的双向调节因子。我们之前报道了B7-1在足细胞中作为人类和动物足细胞损伤和蛋白尿的诱导性中介的新角色。B7-1可以通过阻断抗体如abatacept(CTLA4-Ig)作为靶点，abatacept(CTLA4-Ig)目前用于治疗类风湿关节炎患者。我们获得的新数据表明，CTLA4-Ig的抗蛋白尿作用独立于其对T细胞共刺激的抑制作用，但源于对足细胞的直接作用。我们的新数据进一步表明，足细胞中B7-1的上调通过改变足细胞的结构和功能积极地参与了蛋白尿的发病机制。最重要的是，他们提供了使用阿巴达塞作为抗蛋白尿治疗的理由。在这里，我们建议验证我们的中心假设，即在足细胞中诱导B7-1的表达通过阻断talin介导的足细胞中整合素的激活而参与蛋白尿的发病。我们进一步假设abatacept/CTLA4-Ig和可能的belatacept通过阻断足细胞中的B7-1信号来预防蛋白尿。为了检验这一假设，我们提出了两个具体目标。第一个目标将确定B7-1的机制作用及其阻断对足细胞-基质黏附的影响。特异性目标2将评估B7-1阻滞剂对小鼠的抗蛋白尿治疗潜力。如果我们的假设是正确的，这里提出的工作将在长期内具有广泛的意义，因为它将为B7-1阻断的前瞻性临床研究奠定坚实的理论基础。 蛋白尿患者，包括复发和未复发的FSGS患者。从长远来看，这将使我们能够开发新的疗法，通过阻断足细胞中的B7-1信号来治疗蛋白尿和肾小球硬化。

DESCRIPTION (provided by applicant): B7-1/CD80 is known as a bidirectional regulator of T cell activation and tolerance. We previously reported an unanticipated novel role for B7-1 in podocytes as inducible mediator of podocyte injury and proteinuria in humans and animals. B7-1 can be targeted by blocking antibodies such as Abatacept (CTLA4-Ig), which is currently used for the treatment of patients with rheumatoid arthritis. Our novel data obtained with this grant suggest that the anti-proteinuric action of CTLA4-Ig is independent of its inhibitory action on T cell costimulation but stems from a direct effect on podocytes. Our novel data further suggest that the upregulation of B7-1 in podocytes actively contributes to the pathogenesis of proteinuria by altering podocyte structure and function. Most importantly, they offer a rationale for the use o Abatacept as anti-proteinuric treatment. Here we propose to test our central hypothesis that induction of B7-1 expression in podocytes contributes to the pathogenesis of proteinuria by blocking talin mediated ¿1 integrin activation in podocytes. We further hypothesize that Abatacept/CTLA4-Ig and possible Belatacept prevent proteinuria by blocking B7-1 signaling in podocytes. To test this hypothesis we propose two Specific Aims. The first Aim will define the mechanistic role of B7-1 and the effects of its blockade on podocyte- matrix adhesion. Specific Aim 2 will assess the anti-proteinuric therapeutic potential of B7-1 blockade in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will firmly establish the rationale for a prospective clinical study of B7-1 blockade in patients with proteinuria, including cases of recurrent and non-recurrent FSGS. This should in the long-term enable us to develop novel therapies that tackle proteinuria and glomerulosclerosis by blocking B7-1 signaling in podocytes.