OX40/OX40L interactions in allergen-induced airway inflammation and remodeling

描述（由申请人提供）：此提案描述了一个为期5年的培训计划，以发展实验室医学的学术生涯。主要研究者在加州大学圣地亚哥分校完成了结构化内科住院医师和过敏/免疫学奖学金培训，并被任命为助理教授。他将通过专注的职业发展计划和T细胞共刺激应用于慢性过敏原诱导的气道炎症和重塑的培训来扩展他的科学技能。David Broide博士是加州大学圣地亚哥分校的医学教授，他将指导主要研究者的科学发展。Broide博士是公认的气道炎症和重塑机制的领导者，并在指导发展中的内科科学家方面有着良好的记录。一个由科学家组成的咨询委员会，包括在T细胞生物学和共刺激方面具有专长的Michael Croft博士，将提供职业和项目指导。此外，相关的课程作业、研讨会、期刊俱乐部和特定的实验室技术培训将在加州大学圣地亚哥分校医学系的支持性学术环境中提供充足的受保护的研究时间。该研究项目将重点关注共刺激分子在慢性过敏原诱导的气道炎症和重塑中的作用。克罗夫特博士在拉霍亚过敏和免疫学研究所的实验室发现，TNFR家族成员OX40在急性过敏原诱导的气道炎症以及TH2记忆反应中起着关键作用。拟议的研究将通过敲除、抗体阻断、过继性转移和影像学研究来测试OX40/OX40配体相互作用在慢性过敏原诱导的哮喘和气道重塑小鼠模型中的关键作用。此外，我们将评估OX40对TH2细胞的作用，并与表达OX40L的嗜酸性粒细胞和支气管上皮细胞进行串扰。最后，我们将确定OX40和OX40L在人类哮喘支气管周围样本中的表达，并评估过敏原特异性OX40介导的TH2反应，包括来自外周血的关键信号事件。这些研究对了解慢性哮喘的发病机制和揭示治疗靶点具有直接意义。重要的是，哮喘影响了7%的美国人，在过去的几十年里，患病率急剧上升。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in laboratory medicine. The principle investigator has completed structured internal medicine residency and allergy/immunology fellowship training at the University of California at San Diego and has been appointed as an Assistant Professor. He will expand upon his scientific skills through a focused career development plan and training in T cell costimulation as applied to chronic allergen-induced airway inflammation and remodeling. Dr. David Broide is a professor of medicine at UC San Diego and will mentor the principle investigator's scientific development. Dr. Broide is a recognized leader in mechanisms of airway inflammation and remodeling and has a strong record of mentoring developing physician scientists. An advisory committee of scientists, including Dr. Michael Croft who has expertise in T cell biology and costimulation, will provide career and project guidance. In addition, related course work, seminars, journal clubs, and specific laboratory technique training will accompany ample protected research time in a supportive academic environment in the Department of Medicine at UCSD. The research project will focus on the role of costimulatory molecules in chronic allergen-induced airway inflammation and remodeling. Dr. Croft's laboratory at La Jolla Institute for Allergy and Immunology has discovered a critical role for the TNFR family member OX40 in acute allergen induced airway inflammation, as well as in TH2 memory responses. The proposed studies will test the critical roles of OX40/OX40 ligand interactions in a chronic allergen-induced murine model of asthma and airway remodeling through knockout, antibody- blocking, adoptive transfer, and imaging studies. Additionally, we will evaluate the role of OX40 on TH2 cells and cross talk with eosinophils and bronchial epithelial cells expressing OX40L. Finally, we will determine the expression of OX40 and OX40L in human asthmatic peribronchial samples and evaluate allergen specific OX40-mediated TH2 responses, including key signaling events, from peripheral blood. These studies have direct significance for understanding the mechanisms of chronic asthma and may reveal therapeutic targets. Importantly, asthma affects 7% of people in the United States and prevalence has increased dramatically over the past few decades.