Molecular determinants of lung barrier function

肺屏障功能的分子决定因素

• 批准号: 7256398
• 负责人: MICHAEL H. KOVAL
• 金额: $ 33.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256398
• 关键词: Molecular; determinants; lung; barrier; function

DESCRIPTION (provided by applicant): The ability to survive acute lung injury correlates with the ability to maintain alveolar fluid clearance. Alveolar fluid balance is maintained, in part, by epithelial tight junctions which create a permeability barrier to free diffusion between cells. Transmembrane proteins in the claudin family are a major functional component of tight junctions. There are roughly two dozen mammalian claudins and alveolar epithelial cells use differential expression of multiple claudins to regulate the tight junction barrier. Recent work suggests that alveolar epithelial cells also regulate the process of claudin assembly into tight junctions. However, little is known about the mechanisms that regulate claudin trafficking and assembly in general and by alveolar epithelial cells in particular. Also, the rules governing how different claudins can intermix have not been identified. To define the mechanisms which underlie claudin trafficking, we will use a series of cell and molecular approaches to: 1) define roles for EMP-family proteins in regulating claudin traffic, assembly and barrier function, 2) define intracellular sites for claudin oligomerization and determine motifs regulating heteromeric claudin interactions and 3) identify claudin motifs which determine extracellular head-to-head binding specificity. By defining control points that are critical to regulate alveolar barrier function, these studies are expected to provide a molecular and cell biological basis to help design strategies to prevent the alveolar leak that accompanies lung injury.

描述（由申请人提供）：生存的急性肺损伤的能力与维持肺泡液清除率的能力相关。肺泡流体平衡部分通过上皮紧密连接处维持，从而在细胞之间产生了自由扩散的渗透性障碍。克劳丁家族中的跨膜蛋白是紧密连接的主要功能组成部分。大约有两打哺乳动物的克劳德斯，肺泡上皮细胞使用多种claudins的差异表达来调节紧密的连接屏障。最近的工作表明，肺泡上皮细胞还将克劳丁组装的过程调节为紧密的连接。然而，对于通常，尤其是肺泡上皮细胞调节claudin运输和组装的机制知之甚少。同样，尚未确定有关如何使用不同的Claudins Intermix的规则。为了定义claudin贩运构成的机制，我们将使用一系列细胞和分子方法：1）定义EMP家庭蛋白在调节Claudin流量，组装和屏障功能中定义角色正面的结合特异性。通过定义对调节肺泡屏障功能至关重要的控制点，这些研究有望提供分子和细胞生物学基础，以帮助设计策略，以防止肺损伤伴随肺泡泄漏。