GLOMERULAR EPITHELIAL PROTEIN 1

肾病综合征(NS)是导致发病率和死亡率的重要原因， 尤其是在儿童中。尽管这些细胞的形态变化 与NS相关的肾小球已经被发现35年了，我们现在仍然知道 在大多数情况下，对导致它们的原因没有正确的理解。在……里面 特殊微小病变型NS和先天性NS具有相似的肾小球 病理显示肾小球微细的足突融合 上皮细胞(足细胞)，而在膜性肾病中可能 在大多数情况下，会形成抗体，与抗原发生反应 脚部经过加工，免疫沉淀物聚集成团， 干扰肾小球滤过的功能和结构 障碍。为了在治疗这些疾病方面取得进展，我们需要 从分子角度理解肾小球滤过器的结构 是保持的。为了实现这一目标，我们一直在寻找 被限制在肾小球上，假设它将是 这些分子是不正常的或作为上述的抗原 条件。这项申请关注的是一种新发现的蛋白质， GLEPP1，从其核苷酸序列来看，似乎属于一个家族 一种称为膜蛋白酪氨酸磷酸酶(PTPs)的蛋白质。PTPS 被认为是从外部传递信息的接收器 带到牢房里。由于GLEPP1对于足细胞是唯一的(唯一 到目前为止描述的具有这种特性的蛋白质)，它出现在 在足突形成过程中形成肾小球，并在 作为足突融合的模型，我们认为GLEPP1可能会很好地发挥作用 在调节足突结构和功能方面发挥作用。我们是 因此请求支持以完成克隆和测序 兔GLEPP1，测定其蛋白质结构，确认其 确实起到了磷酸酶的作用，以确定哪些蛋白质是 底物对GLEPP1磷酸酶的作用，最后评价GLEPP1 足突融合两种模型的表达和结构 兔和人类的肾小球疾病也是如此。我们预计会有一个 了解GLEPP1的工作原理将为我们提供重要的新见解 足突结构和功能的调节。此外，我们希望 这些信息将导致新的和更有效的方式 治疗儿童肾病综合征。

Nephrotic syndrome (NS) is an important cause of morbidity and mortality, particularly in children. Although the morphologic changes in the glomerulus associated with NS have been known for 35 years, we still do not have a proper understanding of what causes them in most cases. In particular Minimal Change NS and Congenital NS have similar glomerular pathology showing fusion of the delicate foot processes of the glomerular epithelial cell (podocyte), while in Membranous Nephropathy it is likely that in most cases antibodies are formed that react with an antigen on the foot processes so that clumps of immune deposit accumulate and interfere with the function and structure of the glomerular filtration barrier. To make progress in treating these conditions we need to understand in molecular terms how the structure of the glomerular filter is maintained. To achieve this goal we have looked for molecules which are restricted to the glomerulus with the hypothesis that it will be these molecules that are abnormal or acting as antigens for the above conditions. This application focuses on a newly discovered protein, GLEPP1, which appears from its nucleotide sequence to belong to a family of proteins called membrane protein tyrosine phosphatases (PTPs). PTPs are thought to act as receptors that transmit information from outside to inside the cell. Since GLEPP1 is unique to the podocyte (the only protein so far described with this characteristic) and it appears in the deveeloping glomerulus during foot process formation, and disappears in a model of foot process fusion, we believe that GLEPP1 might well play a role in regulating foot process structure and function. We are therefore requesting support to complete the cloning and sequencing of rabbit GLEPP1, to determine its protein structure, to confirm that it does indeed function as a phosphatase, to determine which proteins are substrates for GLEPP1 phosphatase action, and finally to evaluate GLEPP1 expression and structure in two models of foot process fusion in the rabbit and also in human glomerular diseases. We anticipate that a knowledge of how GLEPP1 works will provide important new insight into the regulation of foot process structure and function. In addition we hope that this information will lead to new and more effective ways of treating nephrotic syndrome in children.