EPIDERMAL GROWTH FACTOR MISLOCATION IN ARPKD

ARPKD 中表皮生长因子的错位

• 批准号: 6194996
• 负责人: Ellis David Avner
• 金额: --
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194996
• 关键词: apical membrane; autosomal recessive trait; biological signal transduction; cell line; cellular pathology; disease /disorder model; epidermal growth factor; growth factor receptors; kidney cell; laboratory mouse; nuclear magnetic resonance spectroscopy; polycystic kidney; protein protein interaction; receptor binding; receptor mediated endocytosis; renal tubule; structural biology

Description: (Taken directly from the application) The formation of epithelial cell polarity is a fundamental process in embryonic development and organogenesis. Polarized epithelia form a physical barrier between the host and external environment essential for homeostasis. Cells of this type maintain distinct apical and basolateral membrane domains by actively regulating the membrane distribution of lipids and proteins as well as the submembraneous cytoskeleton unique to each surface. The apical plasma membrane usually contains proteins required for organ-specific functions. In epithelial cells, which line the lumen of kidney tubule segments, for example, many apical membrane proteins mediate absorption. The basolateral plasma membrane contains most of the "house-keeping" proteins necessary for executing basic cellular mechanisms, including growth regulatory molecules like the EGF receptor. A long-term goal of this project is to understand how different genes which cause polycystic kidney disease allow the EGF receptor to mislocalize to the apical plasma membrane in renal cysts originating in collecting tubules. We also wish to learn how apical EGF receptor mislocalization contributes to pathophysiology in this genetically diverse set of diseases, with an emphasis on autosomal recessive disease. This application has two broad Specific Aims. The first Specific Aim seeks to determine whether there is functional connection between ligand-induced trafficking of EGF receptors located at the apical plasma membrane and signaling output, using newly-developed conditionally immortalized collecting tubule cell lines. A long-term goal of this aim is to identify EGF receptor signaling pathways initiated from the apical surface which may be involved in polycystic kidney disease pathophysiology. The second Specific Aim seeks to define and understand protein interactions mediated by intrinsic motifs in the EGF receptor juxtamembrane domain important for regulating endocytic transport and/or signal transduction. This aim will be achieved with three complementary experimental approaches, using information gained from structural studies and in vitro binding studies to manipulate and analyze protein-protein interactions in vivo. A long-term goal of these studies is to identify novel therapeutic targets to control abnormal trafficking and signaling by EGF receptors mislocalized to the apical plasma membrane in cystic lesions. This project is a collaboration between a cell biologist with broad experience in EGF receptor trafficking and signaling, and a structural biologist experienced in structure-function studies.

描述：（直接摘自申请）上皮细胞极性的形成是胚胎发育和器官发生的基本过程。极化上皮细胞在宿主和外部环境之间形成物理屏障，对于体内平衡至关重要。这种类型的细胞通过主动调节脂质和蛋白质的膜分布以及每个表面独特的膜下细胞骨架来维持不同的顶端和基底外侧膜域。顶端质膜通常含有器官特异性功能所需的蛋白质。例如，在肾小管管腔内的上皮细胞中，许多顶膜蛋白介导吸收。基底外侧质膜含有执行基本细胞机制所需的大部分“看家”蛋白质，包括生长调节分子，如 EGF 受体。该项目的长期目标是了解导致多囊肾病的不同基因如何使 EGF 受体错误定位到源自集合管的肾囊肿的顶端质膜。我们还希望了解顶端 EGF 受体错误定位如何影响这一系列遗传多样性疾病的病理生理学，重点是常染色体隐性遗传病。该应用程序有两个广泛的具体目标。第一个具体目标旨在利用新开发的条件永生化集合管细胞系，确定配体诱导的位于顶端质膜的 EGF 受体运输与信号输出之间是否存在功能联系。该目标的长期目标是确定从心尖表面启动的 EGF 受体信号传导途径，该途径可能参与多囊肾病的病理生理学。第二个具体目标旨在定义和理解 EGF 受体近膜结构域中的内在基序介导的蛋白质相互作用，这对调节内吞转运和/或信号转导很重要。这一目标将通过三种互补的实验方法来实现，利用从结构研究和体外结合研究中获得的信息来操纵和分析体内蛋白质-蛋白质相互作用。这些研究的长期目标是确定新的治疗靶点，以控制囊性病变中错误定位于顶端质膜的 EGF 受体的异常运输和信号传导。该项目是一位在 EGF 受体运输和信号传导方面拥有丰富经验的细胞生物学家和一位在结构功能研究方面经验丰富的结构生物学家之间的合作。