Role of afadin signaling in nephron tubulogenesis

afadin 信号在肾单位肾小管发生中的作用

基本信息

批准号：
9041580
负责人：
DENISE K MARCIANO
金额：
$ 34.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-06 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041580
关键词：
Accounting Acute Renal Failure with Renal Papillary Necrosis Adaptor Signaling Protein Adhesions Apical Binding Biochemical Cell membrane Childhood Chronic Kidney Failure Complex Data Defect Development Developmental Process Diffusion Disease Dysplasia Embryonic Development Epithelial Epithelium Event Face Failure Family GTP Binding Guanosine Triphosphate Phosphohydrolases Health Image Injury Kidney Kidney Diseases Knockout Mice Knowledge Lateral Lead Life Maintenance Mediating Membrane Microdomains Modeling Molecular Monomeric GTP-Binding Proteins Mus Natural regeneration Nephrons PVRL1 Pathway interactions Process Proteins Recruitment Activity Renal function Renal tubule structure Reperfusion Injury Resolution Role Signal Pathway Signal Transduction Staging Structure Surface Testing Three-Dimensional Imaging TimeLine United States Work abstracting adhesion receptor afadin apical membrane base basolateral membrane improved in vivo in vivo regeneration insight knock-down mouse model mutant nectin nectin-3 novel repaired research study restoration reverse genetics three dimensional cell culture trafficking ward

项目摘要

DESCRIPTION (provided by applicant): Role of Afadin Signaling in Nephron Tubulogenesis Project Summary/Abstract Formation of polarized epithelial tubules is central to the structure and function of the kidney. Despite its importance, there is a fundamental gap in understanding the earliest steps in tubulogenesis, namely how epithelia establish apical-basal polarity and generate a central lumen. Continued existence of this gap represents an important problem because, until it is filled, an understanding of developmental abnormalities of the kidney will remain largely incomprehensible. The objective of this application is to elucidate how apical- basal polarity is established and lumen formation initiated, focusing on the role of Afadin signaling in nephron formation. Afadin is an adaptor protein to the Nectin family of adhesion receptors. Our preliminary data identify Afadin as critical for establishing an apical surface and initiating lumen formation in developing mouse nephrons. To further elucidate the cellular and molecular mechanisms that initiate polarity and lumen formation, the proposed studies have three specific aims. The first aim is to characterize molecular steps of lumen formation in vivo and in great detail. These studies will generate a molecular timeline of lumen initiation through subcellular localization of polarity, trafficking, and junctional complexes, and through live imaging of lumen formation in mice. Once characterized, additional studies will begin to assign proteins to different stages in the pathway using mouse models. The second aim is to identify novel molecular mechanisms of apical polarity and lumen formation using an established 3D cell culture model. Specifically the proposed experiments will elucidate a detailed signaling pathway by which Nectins and Afadin initiate lumen formation. The third aim will examine the role of Afadin in tubule regeneration after ischemic injury, emphasizing similarities to the developmental process. Together these studies will delineate fundamental steps in polarity and lumen initiation and provide an improved framework for understanding developmental and acquired disorders of renal tubules.

描述（由申请人提供）：Afadin信号传导在肾小管肾小管中的作用摘要/极化上皮小管的抽象形成对于肾脏的结构和功能至关重要。尽管它的重要性，但在理解微管发生的最早步骤中仍然存在根本的差距，即上皮如何建立顶质极性并产生中央腔。这种差距的持续存在代表了一个重要的问题，因为在填充肾脏的发育异常之前，将在很大程度上难以理解。该应用的目的是阐明如何建立根尖的基础极性并启动管腔形成，重点是阿富丁信号在肾单位形成中的作用。 Afadin是对粘附受体蜜饯家族的衔接蛋白。我们的初步数据确定Afadin对于在发育的小鼠肾脏中建立顶部表面并启动管腔形成至关重要。为了进一步阐明启动极性和管腔形成的细胞和分子机制，提出的研究具有三个特定的目的。第一个目的是表征体内管腔形成的分子步骤，并详细介绍。这些研究将通过极性，运输和连接络合物的亚细胞定位以及小鼠中的管腔形成的实时成像来产生腔内启动的分子时间表。一旦表征，其他研究将开始使用小鼠模型在途径中的不同阶段分配蛋白质。第二个目的是使用已建立的3D细胞培养模型来鉴定顶极性和管腔形成的新分子机制。具体而言，所提出的实验将阐明详细的信号通路，nectins和afadin启动腔形成。第三个目的将检查阿丁蛋白在缺血性损伤后在小管再生中的作用，强调与发育过程的相似之处。这些研究将共同描述极性和管腔启动的基本步骤，并为理解肾小管的发育和获得性疾病提供了改进的框架。