GLOMERULAR EPITHELIAL PROTEIN 1 (GLEPP1)

肾病综合征（NS）是发病和死亡的重要原因， 特别是在儿童中。 虽然在形态学上的变化， 肾小球与NS相关已经知道了35年，我们仍然这样做， 在大多数情况下，他们不知道是什么原因造成的。 在 特殊的微小病变NS和先天性NS具有相似的肾小球 病理学显示肾小球纤细的足突融合 上皮细胞（足细胞），而在膜性肾病中， 在大多数情况下，抗体与抗原反应， 足的过程使得免疫存款聚集， 干扰肾小球滤过的功能和结构 屏障 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 保持不变。 为了实现这一目标，我们寻找分子， 仅限于肾小球，假设它将 这些异常分子或充当上述分子的抗原 条件 这个应用程序的重点是一个新发现的蛋白质， GLEPP1，从其核苷酸序列看属于一个家族， 膜蛋白酪氨酸磷酸酶（PTPs）。 PTPs 被认为是从外界传递信息的受体 到细胞内部。 由于GLEPP1是足细胞所特有的（唯一的 蛋白质迄今为止所描述的这一特点），它出现在 在足突形成过程中形成肾小球， 作为足突融合的模型，我们认为GLEPP 1可能与 调节足突结构和功能的作用。 我们 因此，请求支持完成克隆和测序， 兔GLEPP 1，以确定其蛋白质结构，以证实它 确实起着磷酸酶的作用， GLEPP 1磷酸酶作用的底物，并最终评估GLEPP 1 足突融合的两种模型的表达和结构 兔子和人类肾小球疾病。 我们预计， 了解GLEPP1如何工作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 这些信息将带来新的、更有效的方法， 治疗小儿肾病综合征。

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.