SIGNALING ALLERGIC LUNG DISEASE:NF-KB & T HELPER SUBSETS

这项提议是职业发展计划的一部分，该计划将免疫学课程工作形式的教学与科学研究设计和实施方面的直接指导经验相结合。这些领域的专业知识将为哮喘研究的成功提供必要的组成部分。范德比尔特大学肺脏研究中心和微生物学和免疫学系拥有完成拟议研究项目的必要设施。在这种环境下，导师和教职员工都是公认的资深调查人员。这项研究的长期目标是研究调节特应性哮喘和过敏性疾病的发生和维持的机制。T细胞功能是免疫反应和过敏性疾病易感性的关键决定因素。活化的T细胞可以分化为效应器，其细胞因子谱限于1型(干扰素-γ为主)或2型(IL-4、IL-5为主)模式。1型T细胞效应器用于激活细胞介导的免疫和炎症反应，而2型T细胞效应器参与体液反应，并可能限制或抑制1型反应。效应器反应的性质可以调节疾病状态的出现，如1型糖尿病或哮喘。这些差异细胞因子的表达模式是通过转录机制在T细胞克隆和初级效应细胞中控制的。特定目的1的实验将探讨核因子-kappaB损害1型T细胞效应器功能的机制。作为这一目标的一部分，我将调查克隆性扩张受损的作用并量化细胞因子缺陷。在特定目标2中提出的实验将调查1型T细胞效应器是否需要抗原诱导的呼吸道高反应性的发展。在具体目标3中，我们将使用双TCR模型来确定是否可以通过第二个TCR来偏置效应T细胞谱系，从而改变对抗原诱导的呼吸道高反应性的易感性。这个项目再加上我的导师和合作导师的支持，将为我提供成为一名成功的独立调查员的机会，并将使我能够为提高我们对过敏性疾病过程的理解做出重大贡献。

This proposal is part of a career development plan integrating didactics in the form of course work in immunology with direct, mentored experience in the design and conduct of scientific research. Expertise in these areas will provide the necessary components for a successful career in asthma research. The Center for Lung Research and the Department of Microbiology and Immunology at Vanderbilt University have the necessary facilities to complete the proposed research project. The mentors and faculty in this environment are well recognized, established senior investigators. The long term goal of this research is to investigate the mechanisms regulating the development and maintenance of atopic asthma and allergic diseases. T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma dominant) or type 2 (IL-4, IL-5 dominant) patterns. Type 1 T cell effectors serve to activate cell mediated immunity and inflammatory responses, while type 2 T cell effectors are involved in the humoral response and may limit or inhibit type 1 responses. The nature of an effector response can regulate emergence of disease states such as type 1 diabetes or asthma. These patterns of differential cytokine expression are controlled through transcriptional mechanism in T cell clones and primary effector cells. Experiments in specific aim 1 will investigate the mechanism by which NF-kappaB impairs type 1 T cell effector function. As part of this aim, I will investigate the role of impaired clonal expansion and quantitate cytokine defects. Experiments proposed in specific aim 2 will investigate if type 1 T cell effectors are required for the development of antigen- inducible airway hyperresponsiveness. In specific aim 3 we will use a dual TCR model to determine if an effector T cell repertoire can be biased through a second TCR so as to alter the susceptibility to antigen- induced airway hyperresponsiveness. This program together with the support of my mentor and co-mentor will provide me with the opportunity to become a successful independent investigator and will allow me to make a significant contribution to improving our understanding of allergic disease processes.