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: 8690947
• 负责人: ALEXANDER D VERIN
• 金额: $ 223.84万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690947
• 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）：该程序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。该计划项目赠款的总体目标是更好地理解EC Rhoa/RAC 1平衡中的基本机制以及开发在ALI发展过程中恢复障碍完整性的治疗剂。该计划项目由一支高产专家团队领导，由四个相互关联的项目和3个核心组成。项目1将重点介绍蛋白质硝化作用，作为在EC屏障破坏和ALI开发过程中调节RhoA和RAC 1信号的新机制。提出了分子，细胞，生化和整个动物研究，以进一步阐明硝化在开发新型试剂时改变RhoA和RAC 1核苷酸循环以恢复ALI期间Rhoa/RAC 1平衡的机制。项目2通过重点关注HSP90在调节RhoA激活和下游RhoA信号传导中的作用，将项目2与项目1联系起来，并将比较和对比基于广泛的HSP90抑制剂的治疗可能性与靶向特定蛋白质相互作用的诱饵肽。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激活的治疗作用，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将主要集中在G-毒素，LP和项目4上，我们的研究将详尽研究，以研究G-孔形成毒素，肺炎和溶裂蛋白的屏障破坏性作用。项目4中的研究将阐明RhoA/RAC 1失衡的机制，并专注于增强在G-Im介导的ALI期间恢复这种平衡时没有信号的治疗潜力。两个科学核心（人类细胞和分析）和行政核心以具有成本效益的方式提供了多项目的支持，专业知识和服务，从而大大加强了整个科学计划。可以预见的是，高度综合的项目使用态度的细胞，分子，生化和生理方法，这不仅会增加我们对在革兰氏阴性和革兰氏阴性诱导的ALI期间受到Rhoa和Rac 1受到调节的机制的理解，而且还可以促进新的疾病的发展和疾病的范围，从而促进了一种重大疾病的待遇。