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.

项目摘要 αLPHA-1抗胰蛋白酶（AAT）缺陷（AATD）和慢性阻塞性肺疾病（COPD）是肺部疾病，两者都具有表型特征，包括气流异议和气道粘膜纤毛功能障碍，主要归因于肺气肿，定义空气囊的损坏和扩展的条件肺部，引起呼吸困难 AATD是早期发作的主要遗传原因，通常是吸烟加剧。仍然无法治愈AATD/COPD相关的肺气肿；没有治疗可以扭转对肺部的伤害。 COPD的患病率正在大大增加，警告需要新疗法。缺乏模仿人类疾病的适当动物模型，这是一个限制人和啮齿动物肺之间的结构和功能差异。我们建议使用肺气肿遗传模型的猪与烟一起烟雾（CS）可以提供一致的肺组织改变，这是 AATD/COPD。这种猪模型对于临床前研究将具有很大的价值，并促进创新的治疗方法以减慢，停止或逆转AATD/COPD造成的肺部损害。为此，我们计划产生AATD，这是肺气肿的唯一定义的遗传危险因素。 AATD是由蛋白酶抑制剂（PI）基因的突变，导致血液和肺的AAT水平降低，导致肺中性粒细胞弹性酶对肺组织的分解。我们打算利用我们的新型基因编辑开发具有最普遍和严重的AATD基因型Pi*Zz的猪的平台。根据猪模型与 pi*zz突变基因型将发展肺气肿，这是AATD PI*ZZ的特征突变基因型将暴露于CS，以将AATD表型加强到COPD。 pi*zz 。然后，这个实现这一点突变基因型将通过体内血清学测试来监测，同时评估肺气肿的进展在临床上并在病原学上得到证实。我们认为，如此可靠的大型动物模型 AATD/COPD- 链接的肺气肿将对行业和学术研究产生巨大影响，以开发和测试新的药物和新型治疗方法治疗AATD/COPD相关的肺气肿。