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

该提案是职业发展计划的一部分，该计划将免疫学课程中的教学法与设计和开展科学研究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职业生涯提供必要的组成部分。肺部研究中心和范德比尔特大学的微生物学和免疫学系有必要的设施来完成拟议的研究项目。在这个环境中的导师和教师是公认的，建立了高级调查员。本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展和维持的机制。T细胞功能是免疫应答以及过敏性疾病易感性的关键决定因素。活化的T细胞可以分化成效应物，其细胞因子谱限于1型（IFN-γ显性）或2型（IL-4、IL-5显性）模式。1型T细胞效应子用于激活细胞介导的免疫和炎症反应，而2型T细胞效应子参与体液反应并可限制或抑制1型反应。效应器反应的性质可以调节1型糖尿病或哮喘等疾病状态的出现。这些差异细胞因子表达的模式通过T细胞克隆和初级效应细胞中的转录机制来控制。具体目标1中的实验将研究NF-κ B损害1型T细胞效应子功能的机制。作为这一目标的一部分，我将研究受损的克隆扩增和定量细胞因子缺陷的作用。具体目标2中提出的实验将研究抗原诱导的气道高反应性的发展是否需要1型T细胞效应物。在具体目标3中，我们将使用双TCR模型来确定效应T细胞库是否可以通过第二TCR偏向，以便改变对抗原诱导的气道高反应性的易感性。这个项目加上我的导师和共同导师的支持，将为我提供成为一名成功的独立研究者的机会，并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.