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

• 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
• 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

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 Αα-1抗胰蛋白酶缺乏症和 慢性阻塞性肺疾病(COPD)有 肺部疾病，这两种疾病都有共同的表型特征，包括气流阻塞和呼吸道粘液纤毛 功能障碍，主要归因于肺气肿， 一种定义气囊损伤和增大的状态 肺部，导致呼吸急促 。AATD是早发性COPD的主要遗传原因，通常 因吸烟而加剧的。 AATD/COPD相关性肺气肿仍然没有治愈方法；没有治疗方法 可以逆转对肺部的损害。慢性阻塞性肺病的患病率正在显著增加，需要新的 治疗。 由于缺乏适当的动物模型来模拟人类疾病，这一直是一个制约因素 人和啮齿动物肺的结构和功能差异。 我们建议具有肺气肿遗传模型的猪，联合香烟暴露 烟雾(CS)可提供持续的肺组织改变，这是 AATD/COPD。该猪模型将对临床前研究具有重要价值，并将促进 创新的治疗方法，以减缓、阻止或逆转AATD/COPD对肺的损害。为此，我们 计划生产患有AATD的猪，AATD是唯一确定的肺气肿遗传风险因素。 AATD是由一种 蛋白水解酶抑制物(PI)基因突变，导致血液和肺中AAT水平降低，导致 肺组织被中性粒细胞弹性蛋白酶分解。 我们打算利用我们的新基因编辑技术 开发具有最流行和最严重的AATD基因Pi*ZZ的猪的平台。 相应地，猪模型 与 Pi*ZZ突变基因型会患上肺气肿，这是AATD的一个特征 突变型将暴露于CS，以增强AATD对COPD的表型。PI*ZZ 。然后呢，这个 实现这一点 突变型 将通过体内的血清学测试进行监测，同时评估肺气肿的进展 经临床和病理证实。我们认为，如此可靠的大型动物模型 AATD/COPD- 关联肺气肿将对开发和测试新技术的行业和学术研究产生巨大影响 治疗AATD/COPD相关性肺气肿的药物和新治疗方法。