Chitinases and TFGb in Human Asthma

人类哮喘中的几丁质酶和 TFGb

基本信息

批准号：
7476191
负责人：
Esteban Gonzalez Burchard
金额：
$ 35.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476191
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 Numbers 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 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

项目摘要

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.

哮喘的特点是过敏性气道炎症和气道重塑，这是临床上的基础气流受限、支气管高反应性和恶化易感性的特征。对于哮喘如何发展、过敏原致敏机制以及导致哮喘气道变化在一生中持续存在的因素。在这里我们建议临床研究旨在调查有关几丁质酶和 TGFp 在启动和治疗中的作用的基本问题持续过敏性哮喘。我们将把全面的遗传学研究与详细的转化研究结合起来研究解决几丁质酶和 TGFp 途径基因多态性如何影响的假设过敏原致敏、哮喘易感性和哮喘相关表型的表达。目标1将确定几丁质酶 (AMCase/CHIT1) 中遗传变异的独立和依赖性影响对真菌空气过敏原和其他哮喘结果的敏感性。 CHIT1 和将测试 AMCase 基因与对真菌空气过敏原和其他物质的皮试敏感性的关联。哮喘临床研究网络提供的 1700 例哮喘病例队列中的哮喘表型以及拉丁裔和非裔美国人受试者的独立队列。目标 2 将检验自主性和 26 个 TGFp 通路基因的遗传变异对哮喘和哮喘相关表型的相互作用在几个大型、特征明确、种族多样化的哮喘家庭和病例对照队列中。相关的 SNP 将在独立群体中复制。目标 3 将评估功能目标 1 和 2 中检查的基因和遗传变异的重要性。我们将分析相关基因特定肺室中 CHIT1 和 AMCase 的蛋白表达以及遗传因素的影响剪接变异表达和气道几丁质酶活性水平的变异。我们将确定是否有任何分析的 26 个 TGFβ 通路基因显示哮喘患者肺部的差异表达。我们的目标是基于人类受试者的初步数据，并与项目的科学主题紧密结合 1 和 2. 总之，我们的研究将极大地促进对几丁质酶和 TGFp 家族作用的理解过敏和哮喘领域的成员，可以提出新的治疗方法。简单总结：我们将研究 CHIT1、AMCase 和 TGFp 通路中的遗传变异对不同种族人群中的哮喘和哮喘相关特征。我们还将检查遗传的影响这些基因对哮喘患者肺部基因和蛋白质表达的影响。