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; 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率和发病率的主要原因。对感染的异常宿主反应会导致破坏性感染和广泛的组织损伤，导致器官功能障碍和多器官衰竭。在过去的二十年中，革兰氏阴性细菌（GNB）对抗生素的耐药性的发生率越来越多，与全球的死亡率和重大公共卫生问题有关。无法控制的感染是GNB肺炎诱导的急性呼吸窘迫综合征（ARDS）的关键特征，这是严重败血症的破坏性并发症。由于没有可用的特定治疗方法，因此当前的研究重点是确定新的药物靶标以减少促炎反应。众所周知，免疫系统中蛋白质稳态功能障碍会导致全身炎症的发病机理。蛋白质降解主要由蛋白酶体控制。最近，已经确定了称为免疫蛋白酶体的蛋白酶体的特定亚组在包括抗原呈递在内的炎症反应中起关键作用。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件。然而，尚未揭示免疫蛋白酶体结构组件的分子调节及其在ARDS发病机理中的作用。我们假设去泛素酶USP14决定了免疫蛋白酶体的结构组件，并且抑制免疫蛋白酶体会减少NLPR3炎性体激活和GNB诱导的感染。我们将确定USP14激活调节LPS诱导的免疫蛋白酶体结构组件的分子机制。接下来，我们将确定PKCδ对USP14磷酸化的基础机制，从而促进免疫蛋白酶体的结构组件以及GNB诱导的肺损伤和败血症的严重程度。我们将使用最先进的分子方法，人类样品和临床前动物模型。该数据将通过调节诱导的免疫蛋白酶体结构组装来实现促炎性反应的分子调节，这是为促炎反应的分子调节而奠定了基础，该结构组装在急性细菌感染的发病机理中实施。