Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease

肺部炎症疾病中去泛素化酶对蛋白水解的调节

基本信息

批准号：
9912813
负责人：
Yutong Zhao
金额：
$ 39万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-10 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912813
关键词：
Acids Acute Lung Injury Aftercare Anti-Inflammatory Agents Ants Attenuated Back Bacterial Infections Binding Biological Bleomycin Blood capillaries CD14 gene Cell surface Cells Complex Data Deubiquitinating Enzyme Development Disease Edema Endothelium Endotoxins Enzymes Epithelial Epithelium Etiology Extravasation Focal Infection G-Protein-Coupled Receptors GTP-Binding Proteins Infection Inflammatory Inflammatory Response Injury Interruption Ions LTB4R gene Life Link Lipopolysaccharides Lung Lung Inflammation Lung diseases Lysophosphatidic Acid Receptors Lysosomes Mediating Modeling Mole the mammal Molecular Morbidity - disease rate Organ failure Pathogenesis Pathway interactions Peptides Pharmacology Phosphorylation Play Pneumonia Proteins Pseudomonas aeruginosa Recycling Regulation Regulation of Proteolysis Research Role Scheme Sepsis Severities Shock Signal Transduction System Testing Tissues Ubiquitin Ubiquitination Up-Regulation Virulent base clinical care cytokine cytokine release syndrome endotoxin receptor improved inflammatory lung disease knock-down lung injury mortality neutrophil novel novel therapeutic intervention novel therapeutics pathogen receptor response small molecule ubiquitin isopeptidase ubiquitin-specific protease

项目摘要

Abstract An uncontrolled cytokine storm in lungs leads to detrimental effects such as neutrophil influx, capillary leakage, tissue edema, and organ failure often manifested as pneumonia-induced acute lung injury (ALI). Lysophosphatidic acid receptor 1 (LPA1) is a pro-inflammatory G protein coupled receptor, which induces pro- inflammatory cytokine release through Gα-mediated signaling and interaction with endotoxin receptor, CD14. LPA1 has been implicated in the pathogenesis of lung inflammatory disorders. Knockdown or inhibition of LPA1 attenuates endotoxin- or bleomycin-induced lung injury and sepsis. We discovered that LPA1 stability is regulated in the ubiquitin-lysosome system. Ubiquitin-specific protease 11 (USP11) deubiquitinates and stabilizes LPA1, thus promoting LPA1-modulated pro-inflammatory effects. Knockdown of USP11 reduces LPA1 stability and attenuates both LPA- and LPS-induced lung inflammation. This is the first to demonstrate that destabilizing LPA1 reduces lung inflammation, and deubiquitinating enzyme contributes to the pathogenesis of lung injury. We have developed a small blocking peptide (LDPep) to interrupt the interaction between LPA1 and USP11, which specifically reduces LPA1 protein level, without altering expression of other LPA receptors and USP11 target proteins. LDPep post-treatment lessens endotoxin-induced lung injury and sepsis shock. This project will explore a novel therapeutic approach for treating inflammatory disorders like ALI and sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance in the molecular regulation of pro-inflammatory responses during severe infection. Results from these studies can serve as the basis for further development of pharmacologic agents that destabilize LPA1, thereby reducing severity of inflammatory diseases such as lung injury and sepsis.

抽象的肺部不受控制的细胞因子风暴会导致不良反应，例如中性粒细胞流入、毛细血管渗漏、组织水肿和器官衰竭常表现为肺炎引起的急性肺损伤（ALI）。溶血磷脂酸受体 1 (LPA1) 是一种促炎 G 蛋白偶联受体，可诱导促炎症反应通过 Gα 介导的信号传导以及与内毒素受体 CD14 的相互作用释放炎症细胞因子。 LPA1 与肺部炎症性疾病的击倒或抑制有关。 LPA1 可以减轻内毒素或博来霉素引起的肺损伤和败血症。我们发现 LPA1 稳定性较高。泛素特异性蛋白酶 11 (USP11) 去泛素化和调节。稳定 LPA1，从而促进 LPA1 调节的促炎作用。 LPA1 稳定性并可减轻 LPA 和 LPS 诱导的肺部炎症。这是首次得到证实。破坏 LPA1 的稳定性可减少炎症，而去泛素化酶有助于我们开发了一种小阻断肽（LDPep）来阻断这种相互作用。 LPA1 和 USP11 之间，特异性降低 LPA1 蛋白水平，而不改变其他蛋白的表达 LPA 受体和 USP11 靶蛋白治疗后可减轻内毒素引起的肺损伤和该项目将探索一种治疗炎症性疾病（如脓毒症休克）的新方法。 ALI 和脓毒症的执行将为该领域的重大机制进展奠定基础。这些研究的结果可以说明严重感染期间促炎症反应的分子调节。作为进一步开发破坏 LPA1 稳定性的药物的基础，从而减少肺损伤和败血症等炎症性疾病的严重程度。