Exploring TSLP as a Key Initiator and Novel Therapeutic Target for Asthma

探索 TSLP 作为哮喘的关键引发剂和新治疗靶点

• 批准号: 7485648
• 负责人: BAOHUA ZHOU
• 金额: $ 22.22万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485648
• 关键词: Acute; Allergic; Antibodies; Asthma; Atopic Dermatitis; Attenuated; Bone Marrow; CD4 Positive T Lymphocytes; Chimera organism; Chronic; Daily; Data; Dendritic Cells; Disease; Epithelial Cells; Goals; Hypersensitivity; ITGAX gene; Life; Lung; Modeling; Mus; Palliative Care; Pathogenesis; Patients; Regulation; Relative (related person); Role; Skin; Techniques; Testing; Th2 Cells; airway hyperresponsiveness; airway inflammation; base; clinically significant; design; disorder control; functional disability; human TSLP protein; novel therapeutics; prevent; receptor; research study; therapeutic target

DESCRIPTION (provided by applicant): Asthma is an increasingly common disease that remains poorly understood and difficult to manage. Currently available treatments are palliative and require daily administration for life by some patients. Our goal is to elucidate the roles of thymic stromal lymphopoietin (TSLP) in the pathogenesis of asthma and explore TSLP as a novel therapeutic target to prevent and/or control the disease. Base upon the following facts, we hypothesize that TSLP is the key factor in the pathogenesis of allergic diseases and thus serves as candidate therapeutic target for allergy and asthma. (1) TSLP activates CD11c+ dendritic cells (DCs) which in turn prime na¿ve CD4+ T cells to differentiate into Th2 cells. (2) TSLP is up-regulated in epithelial cells of the lesional skins of atopic dermatitis patients as well as airway epithelial cells of asthma patients. (3) Lung-specific TSLP expression leads to an asthma-like disease while skin-specific expression leads to atopic dermatitis. (4) TSLP receptor deficient (Tslpr-/-) mice failed to develop an asthma-like disease in a mouse asthma model. Based on these data, the experiments designed in this proposal is to: 1. Define the regulation of pulmonary TSLP expression in acute mouse asthma model. We will determine whether presence of Th2 polarized OVA-specific CD4+ T cells and/or OVA-loaded DCs could upregulate TSLP expression in airway epithelial cells upon OVA challenge. 2. Define the functional impairment of Tslpr-/- DCs in OVA-induced asthma model through bone marrow chimera technique. We will also determine the relative contributions of DCs and CD4+ T cells in the pathogenesis of TSLP-induced airway inflammation. 3. Explore TSLP as a novel therapeutic target for asthma. Our recent data showed that administration of an anti-TSLP neutralization antibody at both sensitization and challenge could significantly attenuate airway inflammation in a mouse asthma model. We will optimize the use of the antibody and further test whether TSLP neutralization could reverse pre-established airway inflammation and airway hyperresponsiveness in a chronic mouse asthma model, a study with clinical significance. Project Narrative: Asthma is an increasingly common disease that remains poorly understood and difficult to manage. Currently available treatments are palliative and require daily administration for life by some patients. Our goal is to elucidate the roles of thymic stromal lymphopoietin (TSLP) in the pathogenesis of asthma and explore TSLP as a novel therapeutic target to prevent and/or control the disease.

描述（由申请人提供）：哮喘是一种越来越常见的疾病，但人们对其了解甚少且难以控制。目前可用的治疗是姑息性的，需要一些患者终生每天给药。我们的目标是阐明胸腺基质淋巴生成素（TSLP）在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制哮喘的新治疗靶点。基于以下事实，我们假设TSLP是过敏性疾病发病的关键因素，因此可以作为过敏和哮喘的候选治疗靶点。(1) TSLP激活CD11c+树突状细胞（dc），进而诱导CD4+ T细胞向Th2细胞分化。(2) TSLP在特应性皮炎患者病变皮肤上皮细胞和哮喘患者气道上皮细胞中表达上调。(3)肺特异性表达TSLP导致哮喘样疾病，皮肤特异性表达TSLP导致特应性皮炎。(4)在小鼠哮喘模型中，TSLP受体缺陷（Tslpr-/-）小鼠未发生哮喘样疾病。基于这些数据，本方案设计的实验是：1。明确急性小鼠哮喘模型中肺TSLP表达的调控。我们将确定Th2极化OVA特异性CD4+ T细胞和/或OVA负载dc是否可以上调OVA攻击后气道上皮细胞中TSLP的表达。2. 通过骨髓嵌合体技术确定ova诱导哮喘模型中Tslpr-/- dc的功能损害。我们还将确定dc和CD4+ T细胞在tslp诱导的气道炎症发病机制中的相对贡献。3. 探索TSLP作为治疗哮喘的新靶点。我们最近的数据显示，抗tslp中和抗体在致敏和激发时都可以显著减轻小鼠哮喘模型的气道炎症。我们将优化抗体的使用，并进一步测试TSLP中和是否可以逆转慢性小鼠哮喘模型中预先建立的气道炎症和气道高反应性，这一研究具有临床意义。项目简介：哮喘是一种越来越常见的疾病，但人们对其了解甚少且难以控制。目前可用的治疗是姑息性的，需要一些患者终生每天给药。我们的目标是阐明胸腺基质淋巴生成素（TSLP）在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制哮喘的新治疗靶点。