Investigation of CFTR on sinus and craniofacial development in a CF porcine model

CFTR 对 CF 猪模型鼻窦和颅面发育的影响

• 批准号: 8327696
• 负责人: Eugene H Chang
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327696
• 关键词: 3-Dimensional; Adult; Adverse effects; Affect; Animal Model; Antibiotics; Architecture; Bacteria; Birth; Caucasians; Caucasoid Race; Chloride Ion; Chlorides; Chronic; Chronic Sinusitis; Craniofacial Abnormalities; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Dental; Development; Disease; Electrophysiology (science); Environment; Environmental Risk Factor; Epithelial; Epithelium; Ethics; Exhibits; Face; Family suidae; Foundations; Future; Gallbladder; Genes; Goals; Growth; Health; Human; Image; Imaging technology; In Vitro; Infection; Inflammation; Intestines; Investigation; Knock-out; Lead; Liver; Lung; Lung diseases; Malnutrition; Maxillary Sinus; Modeling; Monitor; Morbidity - disease rate; Mutation; Organ; Pancreas; Paranasal Sinus Diseases; Pathogenesis; Pathology; Patients; Phenotype; Prevention; Regulator Genes; Research; Research Personnel; Respiratory physiology; Role; Sinus; Sinusitis; Site; Sphenoidal sinus; Sweat Glands; Techniques; Testing; Time; Work; airway epithelium; craniofacial; cystic fibrosis patients; disorder prevention; frontal sinus; gene therapy; improved; in utero; in vivo; interest; longitudinal human study; male; mortality; novel; prevent; reproductive

DESCRIPTION (provided by applicant): The overall goal of the investigator is to develop an animal model to test hypotheses that will study the role of airway epithelia in craniofacial development and understand the pathology of sinus disease in Cystic fibrosis (CF). This is the first time an animal model will allow us to investigate the role of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) on craniofacial development and sinus pathology in CFTR knockout (CFTR-/-) and wild-type (CFTR+/+) pigs. The cystic fibrosis pig model is the first large animal model for CF, and our preliminary studies show that the CF pig develops sinusitis, and craniofacial changes similar to human CF. We will utilize advances in imaging technology and 3-dimensional volumetric analysis to investigate changes in paranasal sinus disease and craniofacial growth in WT and CF pigs. We also have the advantage of challenging both WT and CF pigs with bacteria, and observing if infection causes sinus disease and craniofacial changes in pigs. We hypothesize that a lack of CFTR will lead to changes in craniofacial development and sinus pathology in a porcine CF model. To investigate this hypothesis we propose three specific aims. Specific Aim 1: CFTR-/- pigs will have changes in sinus and craniofacial development. Human patients with cystic fibrosis are known to have chronic sinus disease as well as paranasal sinus hypoplasia. Patient with CF typically have maxillary sinus hypoplasia, as well as small or absent frontal and sphenoid sinuses. Because CF patients often have chronic sinus disease, it has been difficult to determine if the genetic defect of CF causes sinus hypoplasia leading to sinus disease, or sinus disease leads to sinus hypoplasia, or if they are independent factors. The CF pig will allow us to study sinus and craniofacial development in the absence of disease at birth and throughout adulthood. Specific Aim 2: CFTR-/- pigs will develop sinus disease prior to lung disease. Human patients with cystic fibrosis develop both sinus and lung disease. Clinicians have investigated the role of sinus disease to the progression of lung disease in humans with cystic fibrosis. The investigation of which comes first, sinus or lung disease has not been answered in humans. If sinus disease does precede lung disease, prevention of sinus disease may improve lung function and reduce morbidity and mortality in CF. The CF pig will allow us to monitor the development of sinus and lung disease in a clean environment and after bacterial challenge. Specific Aim 3: CFTR-/- pigs will have an epithelial defect of impaired chloride transport. We can correct this defect by gene therapy of CFTR to the epithelia. In vitro airway cultures of CF epithelia exhibit defective chloride transport in electrophysiology studies. We hypothesize that we can correct this defect by delivering CFTR to airway epithelia via gene therapy. If this is successful in vitro, we can transition to an in vivo pig model. The CF pig will allow us to target gene therapy in the sinus. This work will serve as a foundation for future treatment and prevention of sinus disease in humans, and may improve lung function and the health of CF patients.

描述（由申请人提供）：研究者的总体目标是开发一种动物模型来检验假设，该假设将研究气道上皮在颅面发育中的作用，并了解窦疾病在囊性纤维化（CF）中的病理学。这是动物模型首次允许我们研究囊性纤维化跨膜电导调节剂（CFTR）对CFTR敲除（CFTR - / - ）和野生型（CFTR+/+）猪中颅面发育和鼻窦病理学的作用。囊性纤维化猪模型是CF的第一个大动物模型，我们的初步研究表明，CF猪会出现鼻窦炎，颅面变化与人类CF相似。我们将利用成像技术和三维体积分析的进步来研究WT和CF猪中偏anas鼻窦疾病和颅面生长的变化。我们还具有挑战细菌WT和CF猪的优势，并观察到感染是否会引起猪的鼻窦病和颅面变化。我们假设缺乏CFTR会导致猪CF模型中颅面发育和鼻窦病理的变化。为了研究这一假设，我们提出了三个具体目标。具体目标1：CFTR - / - 猪会发生鼻窦和颅面发育的变化。囊性纤维化的人类患者已知患有慢性鼻窦疾病和旁鼻窦发育不全。患有CF的患者通常患有上颌窦性发育不全，以及小或不存在的额叶和蝶窦。由于CF患者经常患有慢性鼻窦病，因此很难确定CF的遗传缺陷是否引起鼻窦发育不全导致鼻窦病，或者鼻窦疾病导致鼻窦发育不全，或者它们是独立因素。 CF猪将使我们能够在出生时和整个成年期没有疾病的情况下研究鼻​​窦和颅面发育。具体目标2：CFTR - / - 猪会在肺部疾病之前患上鼻窦病。囊性纤维化的人类患者同时发展鼻窦和肺部疾病。临床医生已经调查了鼻窦疾病对囊性纤维化人类肺部疾病进展的作用。首先进行的调查是，鼻窦或肺部疾病尚未在人类中得到回答。如果鼻窦病在肺部疾病前确实存在，则预防鼻窦病可以改善肺功能，并降低CF的发病率和死亡率。 CF猪将使我们能够在干净的环境和细菌挑战之后监测鼻窦和肺部疾病的发展。特定的目标3：CFTR - / - 猪将具有氯化物转运受损的上皮缺陷。我们可以通过将CFTR的基因治疗纠正这种缺陷。 CF上皮菌的体外气道培养物在电生理学研究中表现出缺陷的氯化物转运。我们假设我们可以通过基因治疗将CFTR传递到气道上皮来纠正这一缺陷。如果在体外成功，我们可以过渡到体内猪模型。 CF猪将允许我们靶向窦中的基因治疗。这项工作将成为未来治疗和预防人类鼻窦病的基础，并可能改善肺功能和CF患者的健康。