Molecular regulation of immunoproteasome assembly in inflammatory diseases

炎症性疾病中免疫蛋白酶体组装的分子调控

• 批准号: 10637422
• 负责人: JING ZHAO
• 金额: $ 62.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637422
• 关键词: 26S proteasome; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Animal Model; Antibiotic Resistance; Antigen Presentation; Attenuated; Bacteremia; Bacteria; Bacterial Infections; Bacterial Pneumonia; Blood specimen; Cell Death; Cell model; Complex; Complication; Data; Development; Disease; Down-Regulation; Endotoxins; Foundations; Functional disorder; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Homeostasis; Human; Immune response; Immune system; Incidence; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Lipopolysaccharides; Lung; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Morbidity - disease rate; Multiple Organ Failure; Organ; Pathogenesis; Patients; Peptide Hydrolases; Phosphorylation; Play; Proteins; Public Health; Regulation; Research; Role; Sampling; Scheme; Sepsis; Severities; Signal Transduction; Stimulus; Subgroup; System; Tissues; Ubiquitin; inhibitor; lung injury; mRNA Expression; mortality; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel therapeutics; pre-clinical; protein degradation; protein kinase C-delta; proteostasis; sepsis induced ARDS; sepsis induced acute lung injury; systemic inflammatory response; ubiquitin isopeptidase

Severe bacterial infections are a major cause of global mortality and morbidity. An aberrant host response to infection leads to destructive inflammation and extensive tissue damage, resulting in organ dysfunction and multi- organ failure. An increasing incidence of gram-negative bacteria (GNB) resistance to antibiotics has been associated with increased mortality and significant public health problems in the world over last two decades. Uncontrollable inflammation is a critical feature of GNB pneumonia-induced acute respiratory distress syndrome (ARDS), a devastating complication of severe sepsis. Since there are no specific treatment available, current research focuses on identifying new drug targets to diminish pro-inflammatory responses. Dysfunction of protein homeostasis in immune system has been known to contribute to the pathogenesis of systemic inflammation. Protein degradation is mainly controlled by the proteasome. Recently, a specific subgroup of the proteasome called the immunoproteasome has been identified to play a critical role in inflammatory responses including antigen presentation. In the preliminary study, we found that endotoxin increases immunoproteasome structural assembly; however, the molecular regulation of immunoproteasome structural assembly and its role in the pathogenesis of ARDS have not been revealed. We hypothesize that deubiquitinase USP14 determines immunoproteasome structural assembly, and that inhibition of the immunoproteasome diminishes NLPR3 inflammasome activation and GNB-induced inflammation. We will determine molecular mechanisms by which USP14 activation regulates LPS-induced immunoproteasome structural assembly. Next, we will determine the mechanisms underlying how the phosphorylation of USP14 by PKCδ promotes immunoproteasome structural assembly and severity of GNB-induced lung injury and sepsis. We will use state-of the art molecular approaches, human samples, and preclinical animal models. The data will lay the foundation for a significant mechanistic advancement regarding the molecular regulation of the pro-inflammatory responses through the modulation of the inducible immunoproteasome structural assembly, which are implicated in the pathogenesis of acute bacterial infection.

严重的细菌感染是全球死亡和发病的主要原因。宿主对感染的异常反应导致破坏性炎症和广泛的组织损伤，导致器官功能障碍和多器官衰竭。在过去二十年中，革兰氏阴性菌（GNB）对抗生素耐药的发病率不断上升，与世界上死亡率上升和重大公共卫生问题有关。不可控制的炎症是GNB肺炎引起的急性呼吸窘迫综合征（ARDS）的一个重要特征，ARDS是严重败血症的一种破坏性并发症。由于没有特定的治疗方法，目前的研究重点是寻找新的药物靶点来减少促炎反应。免疫系统蛋白稳态的紊乱与全身性炎症的发病机制有关。蛋白质的降解主要由蛋白酶体控制。最近，一个被称为免疫蛋白酶体的特定亚群被确定在炎症反应中起关键作用，包括抗原呈递。在初步研究中，我们发现内毒素增加了免疫蛋白酶体的结构组装；然而，免疫蛋白酶体结构组装的分子调控及其在ARDS发病中的作用尚不清楚。我们假设去泛素酶USP14决定了免疫蛋白酶体的结构组装，并且免疫蛋白酶体的抑制减少了NLPR3炎症体的激活和gnb诱导的炎症。我们将确定USP14激活调节lps诱导的免疫蛋白酶体结构组装的分子机制。接下来，我们将确定PKCδ磷酸化USP14如何促进免疫蛋白酶体结构组装和gnb诱导的肺损伤和脓毒症的严重程度的机制。我们将使用最先进的分子方法，人类样本和临床前动物模型。这些数据将为通过调节可诱导的免疫蛋白酶体结构组装来调节促炎反应的分子调控机制的重大进展奠定基础，这与急性细菌感染的发病机制有关。