Lunatic fringe in peripheral T cells alters Notch-mediated Th2 pathology in viral

外周 T 细胞中的疯狂边缘改变了病毒中 Notch 介导的 Th2 病理学

• 批准号: 8509893
• 负责人: Sumanta Mukherjee
• 金额: $ 10万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509893
• 关键词: Address; Adult; Allergens; Allergic; Allergic Disease; Antigen-Presenting Cells; Antiviral Agents; Area; Asthma; Automobile Driving; Award; Bioinformatics; CD4 Positive T Lymphocytes; ChIP-seq; Child; Childhood; Chronic; Chronic Obstructive Airway Disease; Clinical; Cytokine Activation; Cytotoxic T-Lymphocytes; Data; Development; Disease; Environment; Extrinsic asthma; Family; Foundations; Goals; Health; Health Care Costs; Hospitalization; Hospitals; Hypersensitivity; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Interferon Type II; Life; Ligands; Lung diseases; Mediating; Mentors; Molecular; Mucous body substance; Mus; Pathology; Patients; Peripheral; Phase; Population; Production; Pulmonary Pathology; Receptor Activation; Recurrence; Regulation; Relative (related person); Respiratory Syncytial Virus Infections; Respiratory physiology; Respiratory syncytial virus; Role; Severity of illness; Signal Transduction; T cell regulation; T cell response; T-Cell Development; T-Lymphocyte; Training; Up-Regulation; Viral; Virus; Virus Diseases; Visit; Western World; airway hyperresponsiveness; cockroach allergen; cytokine; environmental allergen; glycosyltransferase; in vivo; insight; killings; mouse model; new therapeutic target; notch protein; novel; research study; response; skills; tool

DESCRIPTION (provided by applicant): Childhood allergic asthma has been and still is a growing health problem in the western world. Many children begin to have significant complications from severe asthma due to environmental allergens such as cockroach allergen (CRA) early in life. The clinical manifestations include increased airway hyperreactivity, altered lung function and peribronchial inflammation. In most cases these children develop a chronic pulmonary disorder that results in asthma later in their life. Infection with respiratory syncytial virus (RSV), commonly known as a 'pediatric virus' may be an initiating infection but also exacerbates the pulmonary disease in these children, necessitating hospitalization and frequent recurrent hospital visits adding to the burden of health care costs. RSV also exacerbates disease in susceptible adult populations with existing pulmonary disorders such as asthma and COPD. Thus, viral exacerbation of existing lung diseases remains a serious problem. Previous studies in mice have shown RSV elicits a Th2 inflammatory response with hyper-secretion of mucus and decreased viral clearance causing significant pulmonary pathology. In this proposal RSV exacerbation of an allergen response will be investigated with specific focus on Th2 cytokine associated disease severity. The T cell responses during allergen sensitization or viral infection are dictated by the cytokine environment and through instructive signals from Notch ligand Delta-like 4 (Dll4). The role of Notch in T cell development is well established while its role in peripheral T cell regulation has only begun to be appreciated. Our recent data demonstrated that Dll4 is upregulated on antigen presenting cells following primary RSV infection and results in altered Th2 responses in vivo. Our preliminary studies suggest that Dll4 augments Th2 cytokine production during RSV exacerbation of existing allergic lung disease. This augmented T cell response by Dll4 is due to upregulation of lunatic fringe (LFNG), a glycosyltransferase that enhances Notch receptor activation by ligands belonging to the Delta-like family and inhibits Notch activation by jagged ligands. These preliminary studies provide the rationale for our central hypothesis that increased expression of LFNG in an existing Th2 environment augments Dll4 signaling and enhances Th2 response during viral exacerbation. To further understand the role of LFNG in this disease we propose the following aims - i) identify the specific role of LFNG during viral exacerbation of existing allergic lung disease and ii) determine the molecular mechanisms regulating LFNG in a Th2 environment. Further, we also observed that the expression of notch receptors 1 (N1) and 2 (N2) are specifically increased in T cells under in vitro Th2 conditions that recapitulate an in vivo allergic Th2 environment in mice. Thus our final aim - iii) is to address the regulation of Th2 cytokines by notch receptors in the context of LFNG during viral exacerbation of existing allergic disease.

描述（由申请人提供）：儿童过敏性哮喘在西方世界一直是并且仍然是一个日益严重的健康问题。许多儿童开始有严重的并发症，严重哮喘是由于环境过敏原，如蟑螂过敏原（CRA）在生命的早期。临床表现包括气道高反应性增加、肺功能改变和支气管周围炎症。在大多数情况下，这些儿童发展为慢性肺部疾病，导致哮喘在以后的生活。呼吸道合胞体感染 RSV病毒（通常称为“儿科病毒”）可能是这些儿童的初始感染，但也会加重肺部疾病，需要住院治疗和频繁的反复住院，增加了医疗保健费用的负担。RSV还加重患有现有肺部疾病（如哮喘和COPD）的易感成人人群的疾病。因此，现有肺部疾病的病毒性恶化仍然是一个严重的问题。 先前在小鼠中的研究已经显示RSV激发Th 2炎症反应，伴随粘液分泌过多和病毒清除减少，导致显著的肺部病理学。在本提案中，将研究过敏原应答的RSV恶化，特别关注Th 2细胞因子相关疾病的严重程度。过敏原致敏或病毒感染期间的T细胞应答由细胞因子环境和通过来自Notch配体δ样4（Dll 4）的指导性信号决定。Notch在T细胞发育中的作用已得到充分确立，而其在外周T细胞调节中的作用才刚刚开始被认识。我们最近的数据表明，在原发性RSV感染后，Dll 4在抗原呈递细胞上上调，并导致体内Th 2应答改变。 我们的初步研究表明，在现有的过敏性肺病的RSV恶化期间，Dll 4增强Th 2细胞因子的产生。D114增强的T细胞应答是由于Lunatic fringe（LFNG）的上调，LFNG是一种糖基转移酶，其通过属于Delta样家族的配体增强Notch受体活化并通过锯齿状配体抑制Notch活化。这些初步研究为我们的中心假设提供了基本原理，即在现有的Th 2环境中LFNG表达的增加增强了Dll 4信号传导并增强了病毒加重期间的Th 2应答。为了进一步理解LFNG在这种疾病中的作用，我们提出了以下目标- i）鉴定LFNG在现有过敏性肺病的病毒加重期间的特定作用，和ii）确定在Th 2环境中调节LFNG的分子机制。此外，我们还观察到notch受体1（N1）和2（N2）的表达在体外Th 2条件下在T细胞中特异性增加，所述体外Th 2条件重现小鼠体内过敏性Th 2环境。因此，我们的最终目的- iii）是解决Notch受体对Th 2细胞因子的调节， 在现有过敏性疾病的病毒性加重期间LFNG的背景。