Store Operated Ca2+ Entry: Lung Endothelial Permeability

商店操作的 Ca2 输入：肺内皮渗透性

• 批准号: 6908946
• 负责人: Troy Stevens
• 金额: $ 26.72万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-10 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908946
• 关键词: actins; calcium channel; calcium flux; cell adhesion; cell morphology; cytoskeleton; electrophysiology; gap junctions; laboratory rat; protein protein interaction; respiratory epithelium; spectrin; tissue /cell culture; vascular endothelium; vascular endothelium permeability; vasoconstriction

DESCRIPTION (provided by applicant): Inflammatory mediators induce gaps between endothelial cells that are sufficient to increase tissue edema and facilitate transmigration of circulating blood elements to sites of injury. A rise in cytosolic Ca2+ ([Ca2+]i) triggers the cytoskeletal reorganization, decrease in cell adhesion, and increase in tension that causes gap formation. This [Ca2+]i response to inflammatory mediators is broadly characterized by two phases, including Ca2+ release from intracellular stores and Ca2+ entry across the cell membrane. These phases are inter-related since Ca2+release stimulates Ca2+ entry in a process generally referred to as store operated Ca2+ entry. It is Ca2+ entry and not Ca2+ release that promotes endothelial cell gap formation, although he ion channels that mediate this rise in [Ca2+]i are unknown. Emerging evidence indicates that while inflammatory agonists activate both Ca2+ selective and non-selective cation channels, it is a Ca2+ selective channel that is uniquely coupled to loss of endothelial cell barrier integrity. Moreover, our preliminary data suggest two subunits of the transient receptor potential gene family, so called Trp1 and Trp4, combine to form the molecular basis of this Ca2+ selective channel Trp1 and Trp4 appear to interact directly with the spectrin membrane skeleton and consequently activation of a Trp1 and Trp4 channel provides a Ca2+ source immediately adjacent to cytoskeletal structures that regulate endothelial cell shape. This proposal therefore tests the OVERALL HYPOTHESIS: that activation of a Trp1/r-dependent store operated Ca2+ entry pathway promotes reorganization of the membrane skeleton necessary to increase endothelial permeability. Specific Aim test the related hypotheses that: 1) Trp1 and Trp4 combine to form a Ca2+-selective store operated channel in endothelial cells: 2) Activation of a Trp1/4 channel requires its direct interaction with the spectrin membrane skeleton 3) Ca2+ entry through a Trp1/4 channel disrupts the spectrin-actin interaction and reorganizes f-actin important for increased permeability. Proposed studies are significant because they may reveal a/the ion channel that specifically regulated endothelial cell barrier function. If true, then pharmacological inhibitors of this channel could be developed as a novel anti-inflammatory therapy.

描述（由申请人提供）：炎症介质会引起内皮细胞之间的间隙，而内皮细胞足以增加组织水肿并促进循环的血液元素移动到受伤部位。 胞质Ca2+（[Ca2+] i）的升高会触发细胞骨架的重组，减少细胞粘附，并增加导致间隙形成的张力。 这种[Ca2+]对炎症介质的反应广为特征，包括两个阶段，包括从细胞内存储中释放的Ca2+释放和整个细胞膜的Ca2+进入。 这些阶段相互关联，因为Ca2+释放在通常称为商店操作的Ca2+条目的过程中刺激Ca2+条目。 它是Ca2+进入而不是Ca2+释放，它促进了内皮细胞间隙的形成，尽管介导[Ca2+] I中的这种升高的元素是未知的。 新兴的证据表明，尽管炎症激动剂激活CA2+选择性和非选择性阳离子通道，但它是CA2+选择性通道，与内皮细胞屏障完整性的丧失唯一耦合。 Moreover, our preliminary data suggest two subunits of the transient receptor potential gene family, so called Trp1 and Trp4, combine to form the molecular basis of this Ca2+ selective channel Trp1 and Trp4 appear to interact directly with the spectrin membrane skeleton and consequently activation of a Trp1 and Trp4 channel provides a Ca2+ source immediately adjacent to cytoskeletal structures that regulate endothelial cell shape. 因此，该建议检验了总体假设：TRP1/R依赖性商店操作的Ca2+进入途径的激活促进了增加内皮渗透性所需的膜骨架的重组。 具体目标测试相关的假设：1）TRP1和TRP4在内皮细胞中形成CA2+ - 选择性存储通道：2）激活TRP1/4通道需要与Spectrin膜骨架3）直接相互作用Ca2+通过TRP1/4通道的进入Spectrin-Action-figtion for-and Action contions for-and Action和Reorance Interaction-reorantials ca2+进入。 提出的研究很重要，因为它们可能揭示了特异性调节内皮细胞屏障功能的A/离子通道。 如果是真的，那么该通道的药理抑制剂可以作为一种新型的抗炎疗法发展。