Endothelial Barrier Protection and Repair in Acute Lung Injury

急性肺损伤中的内皮屏障保护和修复

• 批准号: 8298506
• 负责人: Stephen M Black
• 金额: $ 227.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298506
• 关键词: Acute; Acute Lung Injury; Address; Adenosine; Adult Respiratory Distress Syndrome; Alveolar; Animals; Arts; Biochemical; Biochemistry; Blood Vessels; Blood capillaries; Cells; Clinical; Coagulation Process; Complex; Computational Biology; Core Facility; Development; Discipline; Disease; Drops; Endothelial Cells; Endothelium; Environment; Equilibrium; Equipment; Floods; Functional disorder; Goals; Heart failure; Homeostasis; Human; In Vitro; Inflammatory Response; Intercellular Fluid; Intervention; Lead; Left; Link; Mechanical ventilation; Molecular; Molecular Biology; Mus; Nucleotides; Pathology; Patients; Peptides; Permeability; Physiological; Physiology; Plasma; Play; Process; Productivity; Program Research Project Grants; Proteins; Reagent; Regulation; Research; Resources; Respiratory Failure; Role; Scientist; Services; Severities; Signal Transduction; Streptococcus pneumoniae plY protein; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tidal Volume; Tissues; Toxin; Training; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; Work; base; capillary; cost effective; in vivo; inhibitor/antagonist; mortality; multidisciplinary; nitration; novel; novel therapeutic intervention; programs; repaired

DESCRIPTION (provided by applicant): This Program project is focused on the role of vascular endothelial cell (EC) permeability as a key component in acute lung injury (ALI). The overall goals of this Program Project Grant are to develop a better understanding of the mechanisms underlying disturbances in EC RhoA/Rac 1 balance and in developing therapeutic agents that restore barrier integrity during the development of ALI. The Program Project is led by a team of highly productive experts and comprised of four inter-related projects and 3 cores. Project 1 will focus on the role of protein nitration as a newly described mechanism to regulate RhoA and Rac 1 signaling during the development of EC barrier disruption and ALI. Molecular, cellular, biochemical, and whole animal studies are proposed to further elucidate the mechanisms by which nitration alters RhoA and Rac 1 nucleotide cycling while developing novel reagents to restore the RhoA/Rac 1 balance during ALI. Project 2 is thematically linked to Project 1 by focusing on the role of Hsp90 in regulating RhoA activation and downstream RhoA signaling and will compare and contrast the therapeutic possibilities of broad-based Hsp90 inhibitors with decoy peptides that target specific protein interactions. Project 3 continues the focus on RhoA/Rac 1 balance and will focus on the therapeutic effects of adenosine-induced Rac 1 activation and will elucidate new downstream effectors of Rac 1 and determine the therapeutic potential of modulating their expression both in vitro and in vivo. Projects 1-3 will focus predominantly on the G- toxin, LPS and Project 4 will round out our studies to investigate the barrier disruptive effects of the G-i- pore forming toxins, pneumolysin and Lysteriolysin. Studies in Project 4 will elucidate mechanisms of RhoA/Rac 1 imbalance and focus on the therapeutic potential of enhanced NO signaling in restoring this balance during G-imediated ALI. Two scientific cores (Human Cell & Animal and Analytical) and an Administrative Core provide multi-project support, expertise and service in a cost-effective manner leading to significant strengthening of the entire scientific Program. It is anticipated that the highly integrated Projects using stateof- the-art cellular, molecular, biochemical, and physiological approaches that will not only increase our understanding of the mechanisms by which RhoA and Rac 1 are regulated during both gram negative- and gram positive-induced ALI but will facilitate the development of new strategies and targets for the treatment of a disease that has not seen a significant drop in mortality in 40 years.

描述（由申请人提供）：该计划项目的重点是血管内皮细胞（EC）渗透性作为急性肺损伤（ALI）的关键组成部分的作用。该计划项目拨款的总体目标是更好地了解 EC RhoA/Rac 1 平衡紊乱的潜在机制，并开发在 ALI 发展过程中恢复屏障完整性的治疗药物。该计划项目由高产专家团队领导，由四个相互关联的项目和 3 个核心组成。项目 1 将重点关注蛋白质硝化作为一种​​新描述的机制在 EC 屏障破坏和 ALI 发展过程中调节 RhoA 和 Rac 1 信号传导的作用。分子、细胞、生化和整体动物研究旨在进一步阐明硝化改变 RhoA 和 Rac 1 核苷酸循环的机制，同时开发新试剂以恢复 ALI 期间的 RhoA/Rac 1 平衡。项目 2 在主题上与项目 1 相关，重点关注 Hsp90 在调节 RhoA 激活和下游 RhoA 信号传导中的作用，并将比较和对比广泛的 Hsp90 抑制剂与针对特定蛋白质相互作用的诱饵肽的治疗可能性。项目 3 继续关注 RhoA/Rac 1 平衡，并将重点关注腺苷诱导的 Rac 1 激活的治疗效果，并将阐明 Rac 1 的新下游效应子，并确定在体外和体内调节其表达的治疗潜力。项目 1-3 将主要关注 G-毒素、LPS，项目 4 将完善我们的研究，以调查 G-i-孔形成毒素、肺炎球菌溶血素和溶血素的屏障破坏作用。项目 4 的研究将阐明 RhoA/Rac 1 失衡的机制，并重点关注增强的 NO 信号传导在 G 介导的 ALI 期间恢复这种平衡的治疗潜力。两个科学核心（人类细胞和动物和分析）和一个行政核心以具有成本效益的方式提供多项目支持、专业知识和服务，从而显着加强整个科学计划。预计使用最先进的细胞、分子、生物化学和生理学方法的高度集成的项目不仅将增加我们对革兰氏阴性和革兰氏阳性诱导的 ALI 期间 RhoA 和 Rac 1 调节机制的理解，而且将有助于制定新的策略和目标，用于治疗 40 年来死亡率没有显着下降的疾病。