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：
9237362
负责人：
Yutong Zhao
金额：
$ 37.54万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237362
关键词：
Acids Acute Lung Injury Aftercare Anti-inflammatory Ants Attenuated Back Bacterial Infections Binding Biological Bleomycin Blood capillaries CD14 gene Cell surface Cells Complex Data Deubiquitinating Enzyme Development Disease Edema Endotoxins Enzymes Epithelium Etiology Extravasation Focal Infection G-Protein-Coupled Receptors G-substrate 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 capillary clinical care cytokine 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.

抽象的肺中不受控制的细胞因子风暴会导致有害作用，例如中性粒细胞影响，毛细血管泄漏，组织水肿和器官衰竭通常表现为肺炎诱导的急性肺损伤（ALI）。溶物磷脂酸受体1（LPA1）是一种促炎的G蛋白偶联受体，可诱导促疾病通过Gα介导的信号传导和与内毒素受体的相互作用CD14，炎性细胞因子释放。 LPA1在肺部感染疾病的发病机理中已隐含。击倒或抑制 LPA1减弱内毒素或博来霉素诱导的肺损伤和败血症。我们发现LPA1稳定性是在泛素 - 溶酶体系统中受到调节。泛素特异性蛋白11（USP11）去泛素化和稳定LPA1，从而促进LPA1调节的促炎作用。 USP11的敲低减少 LPA1稳定性并减弱LPA和LPS诱导的肺注射。这是第一个证明的破坏LPA1的稳定会减少肺注射，去泛素化酶有助于肺损伤的发病机理。我们已经开发了一个小的阻断肽（LDPEP）来中断相互作用在LPA1和USP11之间，它专门降低了LPA1蛋白水平，而不会改变其他 LPA受体和USP11靶蛋白。 LDPEP治疗减少了内毒素诱导的肺损伤和败血症震动。该项目将探索一种新型的热方法来治疗炎症性疾病阿里和败血症。这些研究的执行将为在严重感染期间促炎反应的分子调节。这些研究的结果可以作为进一步开发破坏LPA1的药物的基础，从而减少炎症性疾病的严重程度，例如肺损伤和败血症。