Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

描述（由申请人提供）：已知B7-1/CD 80是T细胞活化和耐受的双向调节剂。我们先前报道了B7-1在人类和动物足细胞中作为足细胞损伤和蛋白尿的诱导介质的一种意想不到的新作用。B7-1可以通过阻断抗体如阿巴西普（CTLA 4-IG）靶向，阿巴西普目前用于治疗类风湿性关节炎患者。我们通过该资助获得的新数据表明，CTLA 4-IG的抗蛋白尿作用不依赖于其对T细胞共刺激的抑制作用，而是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促进蛋白尿的发病机制。最重要的是，它们提供了使用阿巴西普作为抗蛋白尿治疗的理由。在这里，我们建议测试我们的中心假设，即诱导足细胞中的B7-1表达有助于蛋白尿的发病机制，通过阻断足细胞中talin介导的整合素激活。我们进一步假设阿巴西普/CTLA 4-IG和可能的贝拉西普通过阻断足细胞中的B7-1信号传导来预防蛋白尿。为了验证这一假设，我们提出了两个具体目标。第一个目标是确定B7-1的机制作用及其阻断对足细胞-基质粘附的影响。具体目标2将评估B7-1阻断在小鼠中的抗蛋白尿治疗潜力。如果我们的假设是正确的，那么本文提出的工作将具有广泛的长期意义，因为它将为B7-1阻滞剂的前瞻性临床研究奠定基础。 蛋白尿患者，包括复发性和非复发性FSGS病例。从长远来看，这将使我们能够开发新的治疗方法，通过阻断足细胞中的B7-1信号来解决蛋白尿和肾小球硬化症。

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.