Molecular determinants of lung barrier function

肺屏障功能的分子决定因素

• 批准号: 7147548
• 负责人: MICHAEL H. KOVAL
• 金额: $ 37.08万
• 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/7147548
• 关键词: intracellular transport; laboratory rat; membrane permeability; membrane proteins; molecular assembly /self assembly; protein binding; protein localization; protein structure function; protein transport; respiratory epithelium; respiratory function; tight junctions; tissue /cell culture

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）：急性肺损伤的生存能力与维持肺泡液清除能力相关。肺泡液平衡部分是通过上皮紧密连接维持的，上皮紧密连接为细胞之间的自由扩散形成渗透性屏障。密蛋白家族中的跨膜蛋白是紧密连接的主要功能成分。哺乳动物的紧密连接蛋白大约有两打，肺泡上皮细胞利用多种紧密连接蛋白的差异表达来调节紧密连接屏障。最近的研究表明，肺泡上皮细胞还调节密蛋白组装成紧密连接的过程。然而，人们对密蛋白运输和组装的一般调节机制，特别是肺泡上皮细胞的调节机制知之甚少。此外，尚未确定不同密蛋白如何混合的规则。为了确定密蛋白运输的机制，我们将使用一系列细胞和分子方法来：1) 确定 EMP 家族蛋白在调节密蛋白运输、组装和屏障功能中的作用，2) 确定密蛋白寡聚化的细胞内位点并确定调节异聚密蛋白相互作用的基序，3) 鉴定决定细胞外头对头结合特异性的密蛋白基序。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，以帮助设计预防伴随肺损伤的肺泡渗漏的策略。