ER-Mitochondrial Control of Acute Lung Injury

ER-线粒体对急性肺损伤的控制

• 批准号: 9173789
• 负责人: Fabeha Fazal
• 金额: $ 47.83万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173789
• 关键词: Accounting; Acids; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Alveolar; American; Attenuated; Biochemical; Blood Vessels; Breathing; Cells; Cessation of life; Clinical; Critical Illness; Cytotoxin; Data; Disease; Dominant-Negative Mutation; Dose; Edema; Effectiveness; Electroporation; Endocytosis; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Floods; Functional disorder; GRP78 gene; Gene Transfer; Goals; Image; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Lead; Length of Stay; Lipopolysaccharides; Liposomes; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Mitochondria; Molecular; Molecular Chaperones; Monitor; Mus; Neutrophil Infiltration; Organelles; Outcome; Pathogenesis; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Physiology; Preventive; Proteolysis; Public Health; RNA Interference; Regulation; Research Design; Respiratory Failure; Role; Signal Transduction; Supportive care; Testing; Therapeutic; Therapeutic Intervention; Thrombin; Time; United States; Vascular Diseases; aerosolized; base; cadherin 5; dosage; endoplasmic reticulum stress; improved; in vivo; inhibitor/antagonist; insight; interstitial; knock-down; lung injury; molecular imaging; mortalin; mortality; mouse model; novel; novel therapeutic intervention; prevent; protective effect; response; small hairpin RNA; therapeutic target; treatment strategy; vascular inflammation

Acute lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a common cause of respiratory failure in critically ill patients, and afflicts ~200,000 Americans each year with ~75000 deaths and 3.6 million hospital days. The hallmark of ALI is vascular dysfunction characterized by endothelial cell (EC) inflammation and barrier disruption resulting in inflammatory infiltrates, interstitial edema, alveolar flooding, and ultimately respiratory failure. All current therapies for ALI/ARDS rely on supportive care to improve clinical outcome. No effective drugs have been developed. Thus, there is an urgent need to develop new treatment strategies for ALI/ARDS that are safe, effective, and based on deeper understanding of the mechanisms involved in ALI pathogenesis. Our long-term goal is to identify viable therapeutic targets and mechanisms to limit ALI. The objective of this application is to determine the role of ER chaperone BiP (immunoglobulin heavy chain binding protein) and mitochondrial chaperone mortalin in mediating EC barrier dysfunction and inflammation in ALI and assess the therapeutic benefit of targeting these molecules against ALI. The proposal is based on our novel findings that implicate an important role for BiP and mortalin in mediating inflammatory signaling and barrier disruption in EC and lung PMN infiltration and vascular leak in a mouse model of ALI. Our encouraging data show that pharmacological inhibitor of BiP or mortalin each protects against lung injury. Intriguingly, however, the combined inhibition of BiP and mortalin is effective at much lower dosage of each inhibitor (which alone shows no protective effect) in protecting against LPS-induced lung injury and mortality in mice. These exciting findings have led us to the hypothesis that BiP and mortalin are critical determinants of ALI by their ability to promote EC permeability and inflammation, and that combined inhibition of BiP and mortalin may prove a highly efficacious therapeutic intervention to control ALI. The proposal will address the following aims. Aim 1 will determine (i) the mechanism of BiP regulation of EC permeability and inflammation and (ii) in vivo role of endothelial BiP in causing lung inflammation and injury. Aim 2 will determine (i) the mechanism by which mortalin regulates EC permeability and inflammation and (ii) in vivo role of endothelial mortalin in causing lung inflammation and injury. Aim 3 will evaluate the preventive and therapeutic potential of simultaneous targeting (combined inhibition) of BiP and mortalin against ALI and mortality in mice. These studies will utilize a combination of cellular, molecular, biochemical, pharmacological, imaging, in vivo gene transfer, and lung physiology. The creative integration of in vitro and in vivo studies will provide novel insights into BiP and mortalin regulation of EC inflammation and permeability during ALI and may lead to novel therapeutic interventions to control ALI/ARDS.

急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)是导致呼吸衰竭的常见原因 危重病人，每年折磨着约200,000美国人，约75000人死亡，360万人住院 几天。ALI的特点是血管功能障碍，其特征是内皮细胞(EC)炎症和 屏障的破坏会导致炎症渗透、间质水肿、肺泡淹水，并最终 呼吸衰竭。目前所有治疗ALI/ARDS的方法都依赖于支持性治疗来改善临床结果。不是 已经研制出了有效的药物。因此，迫切需要开发新的治疗策略。 ALI/ARDS是安全、有效的，并且基于对ALI涉及的机制的深入了解 发病机制。我们的长期目标是确定可行的治疗靶点和机制来限制ALI。这个 本应用的目的是确定ER分子伴侣Bip(免疫球蛋白重链结合)的作用 蛋白)和线粒体伴侣蛋白在介导急性肺损伤和炎症的EC屏障功能障碍和炎症中的作用 评估针对ALI的靶向这些分子的治疗益处。这项提议是根据我们的小说提出的 Bip和mortalin在介导炎症信号和屏障中的重要作用 ALI小鼠模型中内皮细胞和肺中性粒细胞浸润和血管渗漏的破坏。我们令人鼓舞的数据 显示Bip或mortalin的药理抑制剂均可保护肺损伤。然而，有趣的是， Bip和mortalin的联合抑制在每种抑制剂的剂量都低得多的情况下有效(单独使用 对脂多糖诱导的小鼠肺损伤和死亡率无保护作用)。这些令人兴奋的东西 研究结果引导我们假设，Bip和mortalin是ALI的关键决定因素，因为它们有能力 促进EC通透性和炎症，Bip和mortalin联合抑制可能被证明是 控制ALI的高效治疗性干预。该提案将解决以下目标。目标1 将确定(I)Bip调节EC通透性和炎症的机制和(Ii)在体内的作用 内皮BIP在引起肺部炎症和损伤中的作用。目标2将决定(I)通过什么机制 Mortalin调节EC通透性和炎症，以及(Ii)内皮细胞mortalin在体内引起肺损伤中的作用 炎症和损伤。目标3将评估同时靶向的预防和治疗潜力 Bip和mortalin对小鼠ALI和死亡率的联合抑制作用。这些研究将利用 细胞、分子、生化、药理、成像、体内基因转移和肺的结合 生理学。体外和体内研究的创造性整合将为BIP和BIP提供新的见解 Mortalin对ALI时内皮细胞炎症和通透性的调节作用并可能导致新的治疗方法 控制ALI/ARDS的干预措施。