Asthma and Allergic Diseases Cooperative Research Center

这是德克萨斯医学中心NIH/NIAID哮喘和过敏性疾病合作研究中心的一项申请，该中心联合了德克萨斯大学安德森癌症中心和贝勒医学院，研究人类胸腺基质淋巴生成素（TSLP）在Th2免疫反应的发展和维持中的作用，Th2免疫反应主导过敏表型。拟议的研究将测试TSLP是发展和维持特应性和哮喘的主要开关的总体假设。TSLP是一种编码在人类染色体5q22 Th2细胞因子基因簇上的造血细胞因子，在人类中主要由上皮细胞和活化的肥大细胞产生，在特应性皮炎和过敏性哮喘中表达。基因工程小鼠变应性疾病模型也支持TSLP在特应性病理生物学中的核心作用。本提案整合了四个研究项目，两个研究核心和一个行政核心，专注于TSLP。项目1将研究人呼吸道上皮细胞和肥大细胞诱导TSLP表达的机制。项目2将确定TSLP激活骨髓树突状细胞的机制。项目3将阐明TSLP激活骨髓树突状细胞增殖Th2效应细胞和记忆细胞的机制。项目4将重点关注炎性T辅助细胞（Thi）在TSLP产生上调中的作用。这些项目将由行政核心、分析研究核心和临床研究核心提供支持。提出的研究应该为过敏性疾病和哮喘的机制提供新的见解，并有可能确定治疗干预的新靶点。

This is an application for a Texas Medical Center NIH/NIAID Asthma and Allergic Diseases Cooperative Research Center that unites the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine to investigate the role of human Thymic Stromal Lymphopoietin (TSLP) in the development and maintenance of the Th2 immune response that dominates the allergic phenotype. The proposed studies will test the overall hypothesis that TSLP is a master switch for developing and maintaining atopy and asthma. TSLP is a hematopoietic cytokine encoded on the human chromosome 5q22 cluster of Th2 cytokine genes, and in humans is produced predominately by epithelial cells and activated mast cells, and is expressed in the context of atopic dermatitis and allergic asthma. Genetically engineered murine models of allergic disease also support a central role for TSLP in the pathobiology of atopy. This proposal integrates four research projects, two research cores and an administrative core focused on TSLP. Project 1 will investigate the mechanisms for induction of TSLP expression by human respiratory epithelial cells and mast cells. Project 2 will determine the mechanisms by which TSLP activates myeloid dendritic cells. Project 3 will elucidate mechanisms by which TSLP activated myeloid dendritic cells propagate Th2 effecter and memory cells. Project 4 will focus on the role of inflammatory T helper cells (Thi) in the upregulation of TSLP production. These projects will be supported by an Administrative Core, an Analytical Research Core, and a Clinical Research Core. The proposed studies should provide new insight into the mechanisms of allergic disease and asthma, and potentially identify new targets for therapeutic intervention.