Endothelial Barrier Protection and Repair in Acute Lung Injury

描述（由申请人提供）：本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。该计划项目资助的总体目标是更好地了解EC RhoA/Rac 1平衡紊乱的机制，并开发在ALI发展过程中恢复屏障完整性的治疗药物。该计划项目由一个高效的专家团队领导，由四个相互关联的项目和三个核心组成。项目1将集中在蛋白质硝化的作用，作为一个新描述的机制，以调节RhoA和Rac 1信号在EC屏障破坏和ALI的发展。分子，细胞，生物化学，和整个动物的研究，提出进一步阐明硝化改变RhoA和Rac 1核苷酸循环的机制，同时开发新的试剂，以恢复RhoA/Rac 1的平衡在ALI。项目2通过关注Hsp 90在调节RhoA激活和下游RhoA信号传导中的作用与项目1主题相关，并将比较和对比基础广泛的Hsp 90抑制剂与靶向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将主要集中于G-毒素、LPS，并且项目4将完善我们的研究以研究G-1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，并关注增强NO信号在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，从而大大加强整个科学计划。预计高度集成的项目使用最先进的细胞，分子，生物化学，和生理学方法，不仅将增加我们对RhoA和Rac 1在革兰氏阴性和革兰氏阳性过程中调节的机制的理解，但这将有助于开发新的策略和目标，用于治疗一种死亡率没有显着下降的疾病，40年

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.