Monoclonal Antibodies and Genetic Elements for Airway Disease

气道疾病的单克隆抗体和遗传元件

基本信息

批准号：
7827314
负责人：
FRANK D. MCKEON
金额：
$ 50万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7827314
关键词：
Address Affect American Antibodies Area Asthma Bronchitis Cell Polarity Cell Surface Proteins Cell membrane Cell surface Cells Cellular biology Chronic Chronic Obstructive Airway Disease Cloning Complex Coupled Cystic Fibrosis Data Disease Disease Progression Elements Extrinsic asthma Fibrosis Gene Expression Generations Genes Genetic Genomics Histology Human Immune response Immunization Knockout Mice Libraries Lung Membrane Proteins Modeling Molecular Molecular Analysis Monitor Monoclonal Antibodies Mus Nuclear Population Proteins Rattus Reagent Regulatory Element Research Role Screening procedure Sorting - Cell Movement Specificity Technology Testing Therapeutic Time Tissues Trachea airway epithelium airway inflammation cell type design empowered gene therapy genetic element glycosylation mouse model novel novel marker promoter public health relevance research study tool vector

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies, 06-HL-109: Generate reagents for studying lung cell biology and disease progression. Chronic airway disease, including COPD, idiopathic fibrosis, bronchitis, asthma, and cystic fibrosis, affects millions of Americans. These diseases involve multiple cell types and undergo complex remodeling over time. There is a tremendous need of new markers and mouse models of these diseases to develop mitigating therapies. This is a proposal to generate both cell-specific and disease-specific monoclonal antibodies using broad immunization strategies combined with targeted screening approaches. In our preliminary, proof-of-concept experiments, we have generated more than 30 monoclonal antibodies specific to ciliated cells of the trachea. Some of these monoclonal antibodies reveal subpopulations of ciliated cells not apparent from histology alone. We now want to greatly expand these efforts to target a broad spectrum of cells from both the upper and lower airways. In addition, we want to identify disease-specific markers by immunizing mice with airway tissues derived from rat models of allergic asthma, COPD, and other chronic conditions. We will then perform molecular characterizations of the target proteins of these monoclonal antibodies, and then introduce GFP into the genomic sequences of their cognate genes to test for cell-specific expression. Finally, we will generate libraries of monoclonal antibodies specific to cell surface proteins of airway epithelia for tools in FACS analysis of airway disease. We anticipate that these libraries of monoclonal antibodies and tissue-specific promoters will become vital tools for the genetic and molecular analysis of airway disease analysis and progression. PUBLIC HEALTH RELEVANCE: 20 million Americans suffer from some form of chronic airway disease. This is a proposal to identify new molecular tools to evaluate the complex tissue changes that accompany these diseases to empower research to understand these changes and design means of reversing them.

描述（由申请人提供）：此申请解决了广泛的挑战领域（06）启用技术，06-HL-109：生成用于研究肺细胞生物学和疾病进展的试剂。慢性气道疾病，包括COPD，特发性纤维化，支气管炎，哮喘和囊性纤维化，会影响数百万美国人。这些疾病涉及多种细胞类型，并且随着时间的推移会进行复杂的重塑。这些疾病的新标记和小鼠模型非常需要发展疗法。这是一项提议，旨在使用广泛的免疫策略与有针对性的筛查方法产生细胞特异性和疾病特异性的单克隆抗体。在我们的初步概念验证实验中，我们已经产生了30多种针对气管纤毛细胞的单克隆抗体。这些单克隆抗体中的某些揭示了仅组织学不明显的纤毛细胞的亚群。现在，我们希望大力扩大这些努力，以针对上下气道的广泛细胞。此外，我们希望通过用源自过敏性哮喘，COPD和其他慢性疾病的大鼠模型的气道组织免疫小鼠来鉴定特异性标记。然后，我们将对这些单克隆抗体的靶蛋白进行分子特征，然后将GFP引入其同源基因的基因组序列中以测试细胞特异性表达。最后，我们将生成针对气道上皮细胞表面蛋白特异性的单克隆抗体文库，以用于气道疾病的FACS分析。我们预计这些单克隆抗体和组织特异性启动子的这些文库将成为气道疾病分析和进展的遗传和分子分析的重要工具。公共卫生相关性：2000万美国人患有某种形式的慢性气道疾病。这是一项建议，旨在确定新的分子工具，以评估伴随这些疾病的复杂组织变化，以增强研究以了解这些变化和设计逆转的方法。