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

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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.