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Studies of a new checkpoint regulator in controlling lung inflammation

控制肺部炎症的新检查点调节剂的研究

基本信息

批准号：
10229265
负责人：
Zhiqiang Zhang
金额：
$ 24.23万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229265
关键词：
Address Affect Air Allergens Area Asthma Autoimmunity Binding Biological Assay Biological Response Modifiers Caspase Cell physiology Cells Chronic Chronic Disease Clinical Clinical Trials Communicable Diseases DNA Methylation DNA mapping Development Disease Down-Regulation Epigenetic Process Epithelial Epithelial Cells Epithelium Extrinsic asthma Family Family member Host Defense Immune Immune response Incidence Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Inhalation Innate Immune Response Innate Immune System Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Interleukin-18 Invaded Investigation Knockout Mice Length Link Lung Lung Inflammation Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Modification Molecular Morbidity - disease rate Mucosal Immune System Mus Natural Immunity Pathway interactions Phase Positioning Attribute Production Proteins Pyroglyphidae Receptor Signaling Respiratory System Rhinovirus Rhinovirus infection SYK gene Scaffolding Protein Services Signal Transduction Site Source Stimulus System Systemic Lupus Erythematosus T-Lymphocyte Technology Testing Therapeutic Tissues Toll-like receptors Ubiquitination Viral Work airway obstruction allergic airway disease allergic airway inflammation anakinra asthma exacerbation asthma model asthmatic patient cell type chromatin modification cytokine histone modification immunoregulation in vivo insight microorganism mortality mouse model multicatalytic endopeptidase complex novel pathogen protein degradation receptor response scaffold selective expression sensor tool ubiquitin-protein ligase

项目摘要

Project Summary Allergic airway disease such as allergic asthma is a T lymphocyte-controlled chronic disease caused by inflammation in the respiratory tracts, and usually results from immune responses to inhaled allergens, and key features include epithelial damage, airflow obstruction and bronchial hyperresponsiveness. Accumulating evidence suggests the involvement of inflammasome activation and IL-1 family cytokines including IL-1α, IL-1β, IL-18 and IL-33 in the development of allergic asthma. Additionally, viral lung epithelial cells (LECs) infections, most frequently with rhinovirus, are predominantly associated with asthma exacerbations promoted by epithelial IL-33. LECs are a physical barrier between allergens and the mucosal immune system. Importantly, after activation, LECs become innate immune-like cells to produce robust proinflammatory cytokines. However, the molecular basis of LECs activation and IL-1 family cytokines production in allergic asthma remains elusive. The innate immune cells use sensors and adaptors to recognize pathogens, resulting in production of cytokines against infections. This immune response must be regulated to effectively control and eliminate invading microorganisms while minimizing tissue inflammation. Ubiquitination has emerged as a pivotal mechanism to control this response in the innate immune system. A key component of the ubiquitination system is E3 ligase to specifically recognize the substrate for modification. We recently found that a tripartite interaction motif (TRIM) family member, E3 ligase TRIM68, is selectively expressed in LECs. Our preliminary studies show that TRIM68 regulates both inflammasome activation and production of full-length IL-33 in LECs after HDM extract-treatment or rhinovirus infection. Clinically, TRIM68 expression is down-regulated, and the production of IL-1 family cytokines including IL-1α, IL-1β, IL-18 and IL-33 is highly elevated in lungs and LECs from allergic asthma patients, suggesting that TRIM68 indeed regulates allergic asthma. However, how TRIM68 expression is controlled by epigenetic modifications allowing responses to environmental stimuli is unknown. TRIM68 binds and induces the proteasome-dependent degradation of scaffold molecules, SYK and CARD9, to inhibit innate immune responses in allergic asthma. But the in vivo function of TRIM68 to regulate lung inflammation has not been studied. We hypothesize that TRIM68 down-regulation in LECs induces IL-1 family cytokines crucial for initial development as well as perpetuation of allergic asthma. We developed three specific aims in this proposal: (1) To dissect molecular pathways that control TRIM68 expression in LECs under normal and inflammatory conditions. (2) To define the mechanism by which TRIM68 inhibits IL-1 inflammation. (3) To investigate in vivo functions of TRIM68 in regulating LECs function in allergic asthma.

项目总结