ER-Mitochondrial Control of Acute Lung Injury

ER-线粒体对急性肺损伤的控制

• 批准号: 9328149
• 负责人: Fabeha Fazal
• 金额: $ 47.96万
• 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/9328149
• 关键词: Acids; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Alveolar; American; Attenuated; Biochemical; Blood Vessels; Breathing; Cations; 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; Inflammasome; 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; Pharmacology; Phenotype; Physiology; Preventive; Proteolysis; Public Health; RNA Interference; Regulation; Respiratory Failure; Role; Signal Transduction; Supportive care; Testing; Therapeutic; Therapeutic Intervention; Thrombin; United States; Vascular Diseases; aerosolized; base; cadherin 5; design; dosage; endoplasmic reticulum stress; improved; in vivo; inhibitor/antagonist; insight; interstitial; knock-down; lung injury; mortalin; mortality; mouse model; novel; novel therapeutic intervention; prevent; prophylactic; 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 重病患者，每年遭受约20万名美国人的折磨，死亡约75000例和360万医院 天。 ALI的标志是血管功能障碍，其特征是内皮细胞（EC）炎症和 导致炎症性浸润，间质水肿，肺泡洪水以及最终导致的障碍破坏 呼吸衰竭。所有目前针对ALI/ARDS的疗法都依赖于支持性护理来改善临床结果。不 有效的药物已经开发出来。因此，迫切需要为 安全，有效且基于对ALI涉及的机制的更深入了解的ALI/ARD 发病。我们的长期目标是确定可行的治疗靶标和机制以限制ALI。这 该应用的目的是确定ER伴侣BIP（免疫球蛋白重链结合）的作用 蛋白质）和线粒体伴侣钟林在介导EC屏障功能障碍和炎症中 评估靶向这些分子针对ALI的治疗益处。该提议是基于我们的小说 这意味着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EC和肺PMN浸润和血管泄漏的破坏。我们令人鼓舞的数据 表明BIP或Mortalin的药理学抑制剂各自保护肺损伤。然而，有趣的是 BIP和Mortalin的联合抑制作用在每个抑制剂的剂量较低（仅此）时有效 在防止LPS诱导的肺损伤和小鼠死亡率中没有保护作用）。这些令人兴奋 调查结果使我们提出了这样的假设，即Bip和Mortalin是ALI的关键决定因素，它们的能力是 促进EC的渗透性和炎症，并且对BIP和Mortalin的联合抑制可能证明是 高效控制ALI的治疗干预措施。该提案将解决以下目标。目标1 将确定（i）EC渗透性和炎症的BIP调节机制以及（ii）体内作用 内皮BIP引起肺部炎症和损伤。 AIM 2将确定（i）的机制 Mortalin调节EC的渗透性和炎症以及（II）内皮雌林在引起肺中的体内作用 炎症和伤害。 AIM 3将评估同时定位的预防和治疗潜力 （联合抑制）BIP和Mortalin对小鼠的ALI和死亡率。这些研究将利用 细胞，分子，生化，药理学，成像，体内基因转移和肺的结合 生理。体外和体内研究的创造性整合将为BIP和 在ALI期间，Mortalin的EC炎症和渗透性调节，可能导致新的治疗性 控制ALI/ARDS的干预措施。