The Role of Nephronectin in Glomerular Development and Function

项目摘要： 肾小球基底膜（GBM）形成肾小球的关键组分，并且 由许多蛋白质组成，其中许多蛋白质的功能尚不清楚。大部分 GBM位于足细胞和内皮细胞之间，然而，它也直接与 系膜细胞，一种周细胞样的、可收缩的支持细胞。人们对这个个体知之甚少 参与这种相互作用的GBM蛋白以及这些相互作用在肾小球疾病中的作用 在整个发育过程中和成年期的结构和功能。在初步研究中， 鉴定了一种新的含有GBM蛋白肾连蛋白的GBM-系膜细胞粘附。我们 发现肾连蛋白对肾小球簇的发育至关重要，并且在 维持肾小球结构。因此，我们建议：（1）确定 肾连蛋白在肾小球形成的各个阶段，2）测试其在介导稳定性中的作用， 成熟肾脏的肾小球结构，以及3）剖析肾连接蛋白-整合素信号传导的作用 在培养的细胞中。通过这些研究，我们将大大扩展我们对GBM的理解- 系膜细胞相互作用获得这些相互作用及其功能的分子知识 将是理解肾小球生物学的关键一步，并可能有助于定向治疗， 治疗肾小球疾病

Project abstract: The glomerular basement membrane (GBM) forms a critical component of glomeruli, and is comprised of numerous proteins, many of whose individual functions are unknown. Much of the GBM is located between podocytes and endothelia, however, it also interacts directly with mesangial cells, a pericyte-like, contractile, support cell. Very little is known about the individual GBM proteins involved in this interaction and the role these interactions play in glomerular structure and function throughout development and in adulthood. In preliminary studies, we have identified a novel GBM-mesangial cell adhesion that contains the GBM protein nephronectin. We find that nephronectin is essential for development of the glomerular tuft, and also plays a role in maintenance of glomerular structure. We therefore propose to 1) determine the role of nephronectin in various stages of glomerulogenesis, 2) test its role in mediating stability of glomerular structure in mature kidneys, and 3) dissect the role of nephronectin-integrin signaling in cultured cells. Through these studies, we will greatly expand our understanding of GBM- mesangial cell interactions. Gaining molecular knowledge of these interactions and their function will be a critical step to understanding glomerular biology, and may contribute to directed therapies for glomerular disease.