Chitinases and TFGb in Human Asthma

人类哮喘中的几丁质酶和 TFGb

• 批准号: 7798937
• 负责人: Esteban Gonzalez Burchard
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7798937
• 关键词: Acetylglucosamine; Address; Affect; African American; Allergens; Allergic; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Autopsy; Base Pairing; Binding; Biology; Biopsy; Cell Surface Receptors; Cell Wall; Characteristics; Chitin; Chitinase; Clinical; Clinical Research; Code; Custom; DNA Resequencing; Data; Epithelial; Epithelial Cells; Extrinsic asthma; Family; Family member; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Homeostasis; Human; Hydrolysis; Hypersensitivity; Hypersensitivity skin testing; Individual; Inflammatory; Introns; Latino; Lung; Mexican; Outcome; Pathway interactions; Phenotype; Phosphorylation; Population; Population Heterogeneity; Predisposition; Protein Isoforms; Puerto Rican; RNA Splicing; Regulatory Element; Relative (related person); Resources; Risk; Role; Sampling; Severities; Signal Transduction; Smad Proteins; Smad protein; Stimulus; Structure of parenchyma of lung; Testing; Tissue Banking; Tissue Banks; Variant; acidic mammalian chitinase; airborne allergen; airway hyperresponsiveness; airway remodeling; allergic airway inflammation; asthmatic airway; base; case control; cohort; cytokine; fungus; gain of function; gene interaction; genetic variant; high throughput screening; human subject; macrophage; novel; promoter; protein expression; trait; translational study

Asthma is characterized by allergic airway inflammation and airway remodeling which underlie the clinical characteristics of airflow limitation, bronchial hyperresponsiveness, and susceptibility to exacerbation. Important questions remain for how asthma develops, the mechanisms of allergen sensitization, and the factors that contribute to the persistence of asthmatic airway changes over a lifetime. Here we propose clinical studies to investigate fundamental questions about the role of chitinases and TGFp in initiating and perpetuating allergic asthma. We will combine comprehensive genetic studies with detailed translational studies to address hypotheses for how polymorphisms in chitinase and TGFp pathway genes influence allergen sensitization, asthma susceptibility and expression of asthma-related phenotypes. Aim 1 will determine the independent and dependent effects of genetic variants in chitinases (AMCase/CHIT1) on sensitization to fungal aeroallergens and other asthma outcomes. Genetic variants in the CHIT1 and AMCase genes will be tested for association with skin test sensitivity to fungal aeroallergens and other asthma phenotypes in a cohort of 1700 asthma cases provided by the Asthma Clinical Research Network and independent cohorts of Latino and African American subjects. Aim 2 will examine the autonomous and interactive effects of genetic variants in 26 TGFp pathway genes on asthma and asthma-related phenotypes in several large, well-characterized, ethnically diverse asthma family based and case-control cohorts. Associated SNPs will be replicated in independent populations. Aim 3 will evaluate the functional significance of the genes and genetic variants examined in Aims 1 and 2. We will analyze the relative gene and protein expression of CHIT1 and AMCase in specific lung compartments and the effects of genetic variants on expression of splice variants and levels of airway chitinase activity. We will determine if any of the 26 TGFp pathway genes analyzed show differential expression in the lung in asthma. Our aims are founded on preliminary data from human subjects and integrate closely with the scientific themes of projects 1 and 2. Together, our studies will greatly advance understanding of the roles of chitinases and TGFp family members in allergy and asthma and could suggest novel treatment approaches. Lay summary: We will examine the effect of genetic variation in the CHIT1, AMCase and TGFp pathway on asthma and asthma related traits in ethnically diverse populations. We will also examine the effect of genetic variation in these genes on gene and protein expression in the lungs of subjects with asthma.

哮喘的特征是过敏性气道炎症和气道重塑，这是临床的基础 气流限制，支气管高反应性和对加剧的敏感性的特征。 关于哮喘如何发展，过敏原敏化的机制以及 导致哮喘气道持续存在的因素在一生中变化。我们在这里提出 临床研究以调查有关几丁质酶和TGFP在启动和 永久性过敏性哮喘。我们将结合全面的遗传研究与详细的翻译 研究涉及几丁质酶和TGFP途径基因中的多态性如何影响的假设 过敏原敏化，哮喘敏感性和与哮喘相关表型的表达。目标1意志 确定几丁质酶（amcase/Chit1）对遗传变异的独立和依赖性影响 对真菌气溶胶和其他哮喘结果的敏感性。 Chit1中的遗传变异和 amcace基因将接受测试，以与对真菌气溶胶和其他其他的皮肤测试敏感性相关 哮喘临床研究网络提供的1700例哮喘病例的哮喘表型 以及拉丁裔和非裔美国人的独立人群。 AIM 2将检查自主和 26 TGFP途径基因中遗传变异对哮喘和哮喘相关表型的互动效应 在几个大型，良好的，种族多样化的哮喘科和病例对照人群中。 相关的SNP将在独立人群中复制。 AIM 3将评估功能 在目标1和2中检查的基因和遗传变异的重要性。我们将分析相对基因 以及特定肺部室中Chit1和amcase的蛋白质表达以及遗传的影响 关于剪接变体表达和气道几丁质活性水平的变体。我们将确定是否有 分析的26个TGFP途径基因在哮喘中显示肺中的差异表达。我们的目标是 建立在人类受试者的初步数据上，并与项目的科学主题紧密整合 1和2。一起，我们的研究将大大提高对几丁质酶和TGFP家族的作用的理解 过敏和哮喘的成员，可以提出新颖的治疗方法。 摘要摘要：我们将研究CHIT1，AMCASE和TGFP途径对遗传变异的影响 种族多元化种群中哮喘和哮喘与哮喘相关的特征。我们还将检查遗传的影响 这些基因对哮喘受试者肺中基因和蛋白质表达的变异。