ER-Mitochondrial Control of Acute Lung Injury

ER-线粒体对急性肺损伤的控制

基本信息

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
项目类别：
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

项目摘要

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）是呼吸衰竭的常见原因危重病人，每年困扰约 20 万美国人，约 75,000 人死亡，360 万人住院天。 ALI 的标志是血管功能障碍，其特征是内皮细胞 (EC) 炎症和屏障破坏导致炎症浸润、间质水肿、肺泡充盈，最终呼吸衰竭。目前所有的 ALI/ARDS 疗法都依赖于支持性护理来改善临床结果。不已经开发出有效的药物。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 所涉及机制的更深入了解发病。我们的长期目标是确定可行的治疗靶点和机制来限制 ALI。这本申请的目的是确定 ER 伴侣 BiP（免疫球蛋白重链结合蛋白）和线粒体伴侣 mortalin 介导 ALI 和炎症中的 EC 屏障功能障碍和炎症评估针对 ALI 的这些分子的治疗效果。该提案是根据我们的小说改编的研究结果表明 BiP 和 mortalin 在介导炎症信号传导和屏障中发挥重要作用 ALI 小鼠模型中 EC 和肺 PMN 浸润和血管渗漏的破坏。我们令人鼓舞的数据表明 BiP 或 mortalin 的药理学抑制剂均可防止肺损伤。然而有趣的是， BiP 和 mortalin 的联合抑制在每种抑制剂剂量低得多的情况下是有效的（单独使用表明没有保护作用），以防止 LPS 诱导的小鼠肺损伤和死亡。这些激动人心的研究结果使我们得出这样的假设：BiP 和 mortalin 是 ALI 的关键决定因素，因为它们能够促进 EC 通透性和炎症，BiP 和 mortalin 的联合抑制可能证明控制 ALI 的高效治疗干预。该提案将实现以下目标。目标1 将确定 (i) BiP 调节 EC 通透性和炎症的机制，以及 (ii) 的体内作用内皮 BiP 引起肺部炎症和损伤。目标 2 将确定 (i) 的机制 mortalin 调节 EC 通透性和炎症，以及 (ii) 内皮 mortalin 在引起肺损伤中的体内作用炎症和损伤。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）。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组合生理。体外和体内研究的创造性整合将为 BiP 和 mortalin 对 ALI 期间 EC 炎症和通透性的调节，可能会带来新的治疗方法控制 ALI/ARDS 的干预措施。