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

OX40/OX40L 在过敏原诱导的气道炎症和重塑中的相互作用

• 批准号: 7989358
• 负责人: TAYLOR A DOHERTY
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989358
• 关键词: Acute; Adoptive Transfer; Advisory Committees; Affect; Allergens; Antibodies; Antigen-Presenting Cells; Asthma; Biopsy Specimen; Blocking Antibodies; Bone Marrow; California; Cells; Cellular biology; Chimera organism; Chronic; Coculture Techniques; Communication; Development; Development Plans; Environment; Epithelial; Epithelial Cells; Event; Family; Family member; Fellowship; Fibrosis; Flow Cytometry; Gene Expression; Growth Factor; Human; Hypersensitivity; Image; Immunology; In Situ Hybridization; In Vitro; Individual; Inflammation; Inflammatory; Institutes; Internal Medicine; Journals; Knock-out; Laboratories; Ligands; Lung; Lung Inflammation; Maintenance; Mediating; Medicine; Memory; Mentors; Metaplasia; Modeling; Mucous body substance; Mus; Myofibroblast; Peripheral; Physicians; Play; Prevalence; Process; Program Development; Relative (related person); Research; Research Personnel; Research Project Grants; Residencies; Role; Sampling; Scientist; Signal Transduction; Smooth Muscle; Specimen; Structure; T-Cell Proliferation; T-Lymphocyte; TNF gene; TNFSF4 gene; Testing; Time; Training; Training Programs; Training Technics; Tumor Necrosis Factor Receptor; United States; Universities; Work; airway inflammation; airway remodeling; angiogenesis; asthmatic airway; bronchial epithelium; career; career development; cell type; cytokine; eosinophil; in vivo; mast cell; mouse model; muscle form; peripheral blood; professor; response; skills; therapeutic target; tumor necrosis factor ligand superfamily member 4; tumor necrosis factor receptor superfamily member 4

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.

描述（由申请人提供）：该提案描述了一个为期 5 年的检验医学学术职业发展培训计划。主要研究者已在加州大学圣地亚哥分校完成了结构化内科住院医师培训和过敏/免疫学进修培训，并被任命为助理教授。他将通过专注的职业发展计划和 T 细胞共刺激培训（应用于慢性过敏原诱导的气道炎症和重塑）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，将指导首席研究员的科学发展。 Broide 博士是气道炎症和重塑机制领域公认的领导者，在指导医师科学家发展方面拥有良好的记录。一个由科学家组成的咨询委员会，包括拥有 T 细胞生物学和共刺激专业知识的 Michael Croft 博士，将提供职业和项目指导。此外，相关课程作业、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。该研究项目将重点研究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。拉霍亚过敏和免疫学研究所的 Croft 博士实验室发现 TNFR 家族成员 OX40 在急性过敏原诱导的气道炎症以及 TH2 记忆反应中发挥着关键作用。拟议的研究将通过敲除、抗体阻断、过继转移和成像研究来测试 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 细胞的作用以及与表达 OX40L 的嗜酸性粒细胞和支气管上皮细胞的交互作用。最后，我们将测定人哮喘支气管周围样本中 OX40 和 OX40L 的表达，并评估外周血中过敏原特异性 OX40 介导的 TH2 反应，包括关键信号传导事件。这些研究对于了解慢性哮喘的机制具有直接意义，并可能揭示治疗靶点。重要的是，哮喘影响了 7% 的美国人，并且患病率在过去几十年中急剧增加。