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

项目摘要 α-1抗胰蛋白酶（AAT）缺乏症（AATD）和 慢性阻塞性肺疾病（COPD） 肺部疾病，这两种疾病具有共同的表型特征，包括气流阻塞和气道粘膜纤毛 功能障碍，主要归因于肺气肿， 一种确定气囊损伤和扩大的情况 肺的呼吸困难 . AATD是早发性COPD的主要遗传原因， 因吸烟而恶化。 AATD/COPD相关肺气肿仍然无法治愈;没有治疗方法 可以逆转肺部的损伤慢性阻塞性肺病的患病率显著增加，需要新的 治疗 由于缺乏合适的模拟人类疾病的动物模型， 人类和啮齿类动物肺部的结构和功能差异。 我们提出，具有肺气肿遗传模型的猪，结合暴露于香烟， 吸烟（CS）可以提供一致的肺组织改变， AATD/COPD。该模型的建立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，停止或逆转AATD/COPD对肺部造成的损害。为此我们 计划生产AATD猪，AATD是肺气肿的唯一定义的遗传风险因素。 AATD是由一种 蛋白酶抑制剂（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。 我们打算利用我们新的基因编辑技术 平台开发具有最普遍和严重的AATD基因型PI*ZZ的猪。 因此，猪模型 与 PI*ZZ突变基因型将发展为肺气肿，这是AATD PI*ZZ的特征性特征 突变基因型将暴露于CS以强化AATD表型为COPD。PI*ZZ .今天 实现这一 突变基因型 将通过体内血清学检测进行监测，同时评估肺气肿的进展 临床和病理形态学证实。我们相信，这种可靠的大型动物模型， AATD/COPD- 连锁肺气肿将对工业和学术研究产生巨大影响，以开发和测试新的 治疗AATD/COPD相关肺气肿的药物和新的治疗方法。

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.