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

描述(申请人提供)：儿童过敏性哮喘在西方世界一直是，现在仍然是一个日益严重的健康问题。由于蟑螂过敏原(CRA)等环境过敏原，许多儿童在幼年就开始出现严重哮喘的严重并发症。临床表现包括呼吸道高反应性增强、肺功能改变和支气管周炎症。在大多数情况下，这些儿童会发展成一种慢性肺部疾病，导致他们晚年的哮喘。呼吸道合胞病毒感染 呼吸道合胞病毒(RSV)，俗称“儿科病毒”，可能是一种起始感染，但也会加重这些儿童的肺部疾病，需要住院治疗和频繁的住院治疗，增加了医疗费用的负担。RSV还会加重患有哮喘和慢性阻塞性肺病等肺部疾病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。以前在小鼠身上的研究表明，RSV引起Th2炎症反应，粘液过度分泌，病毒清除减少，导致明显的肺部病理。在这项提案中，将研究RSV对过敏原反应的恶化，并特别关注Th2细胞因子相关疾病的严重程度。变应原致敏或病毒感染期间的T细胞反应由细胞因子环境和Notch配体Delta-like 4(DLL4)发出的指示信号决定。Notch在T细胞发育中的作用已经确定，而它在外周T细胞调节中的作用才刚刚开始被认识到。我们最近的数据表明，在原发RSV感染后，DLL4在抗原提呈细胞上表达上调，并导致体内Th2反应的改变。我们的初步研究表明，在现有过敏性肺部疾病的RSV加重期间，DLL4增加了Th2细胞因子的产生。DLL4的这种增强的T细胞反应是由于疯狂边缘(Lfng)的上调，Lfng是一种糖基转移酶，它可以增强Delta样家族的配体对Notch受体的激活，并抑制锯齿状配体对Notch的激活。这些初步研究为我们的中心假设提供了理论基础，即在现有的Th2环境中，Lfng的表达增加会增强DLL4信号，并在病毒加重期间增强Th2反应。为了进一步了解Lfng在本病中的作用，我们提出了以下目标：i)确定Lfng在现有过敏性肺疾病病毒加重过程中的特定作用；ii)确定Th2环境中调节Lfng的分子机制。此外，我们还观察到，在体外Th2条件下，T细胞中Notch受体1(N1)和2(N2)的表达特异性增加，这概括了小鼠体内过敏的Th2环境。因此，我们的最终目标-III)是解决Th2细胞因子的调节由Notch受体在 Lfng在现有过敏性疾病的病毒恶化期间的背景。

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.