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Development of swine model of COPD by integrating genetic and environmental risk factors

整合遗传和环境风险因素开发慢阻肺猪模型

基本信息

批准号：
9348158
负责人：
Tamene Melkamu
金额：
$ 39.87万
依托单位：
RECOMBINETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2020-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348158
关键词：
Affect Air Air Sacs Alleles American Anatomy Animal Model Animals Basic Science Biological Assay Biological Markers Blood Cause of Death Cavia Cells Characteristics Chromatin Chronic Bronchitis Chronic Obstructive Airway Disease Clinic Clinical Clinical Chemistry Clinical Trials Cloning Complex Development Disease Dyspnea Elasticity Engineering Environmental Risk Factor Environmental Tobacco Smoke Enzymes Event Family suidae Fibroblasts Functional disorder Generations Genes Genetic Genetic Engineering Genetic Models Genetic Risk Genotype Hamsters Heart Human Individual Industry Inflammation Leukocyte Elastase Link Liver diseases Lung Lung diseases Maintenance Malignant Neoplasms Methods Miniature Swine Modeling Modification Monitor Mus Mutation Nicotine Obstruction Oryctolagus cuniculus Pathogenesis Pathology Patients Penetrance Phenotype Physiological Physiology Population Positioning Attribute Preclinical Testing Prevalence Protease Inhibitor Pulmonary Emphysema Pulmonary Hypertension Rattus Research Respiratory Failure Respiratory System Rodent Role Serologic tests Serum Shortness of Breath Small Business Innovation Research Grant Structure of parenchyma of lung System Testing Tissues Translations Transplantation United States airway remodeling cigarette smoking cigarette smoking cost early onset environmental tobacco smoke exposure genetic risk factor human disease in vivo innovation mutant neutrophil novel novel therapeutic intervention novel therapeutics pig genome pre-clinical research prototype regenerative therapy tissue regeneration transcription activator-like effector nucleases translational medicine

项目摘要

PROJECT SUMMARY Αlpha-1 antitrypsin (AAT) deficiency (AATD) and Chronic Obstructive Pulmonary Disease (COPD) are lung diseases, both of which share phenotypic features, including airflow obstruction and airway mucociliary dysfunction, attributed primarily to emphysema, a condition that defines damage and enlargement of the air sacs of the lungs, causing breathlessness . AATD is the major genetic cause of early-onset COPD, typically exacerbated by cigarette smoking. There is still no cure for AATD/COPD-associated emphysema; no treatment can reverse the damage to the lungs. Prevalence of COPD is increasing significantly, warranting need for new therapies. Lack of a proper animal model that mimics the human disease has been a constraint, owing to structural and functional differences between human and rodent lungs. We propose that pigs with a genetic model of emphysema, in conjunction with exposure to cigarette smoke (CS) could provide consistent pulmonary tissue alterations that are characteristic features of AATD/COPD. This swine model will be of great value for pre-clinical research and facilitate development of innovative treatments to slow, stop or reverse the damage to the lungs caused by AATD/COPD. For that, we plan to generate pigs with AATD, the only defined, genetic risk factor of emphysema. AATD is caused by a mutation of the protease inhibitor (PI) gene, resulting in a reduced level of AAT in blood and lung, leading to breakdown of the lung tissue by the enzyme neutrophil elastase. We intend to utilize our novel gene-editing platform to develop swine with the most prevalent and severe AATD genotype, PI*ZZ. Accordingly, the pig model with the PI*ZZ mutant genotype will develop emphysema, a characteristic feature of AATD PI*ZZ mutant genotype will be exposed to CS to intensify the AATD phenotype to COPD. PI*ZZ . Then, this Realization of this mutant genotype will be monitored by serological testing in vivo, while progression of emphysema is evaluated clinically and confirmed pathomorphlogically. We believe that such a reliable large animal model of AATD/COPD- linked emphysema will have tremendous impact on industry and academic research to develop and test new drugs and novel therapeutic approaches to treat AATD/COPD-associated emphysema.

项目总结