Twenty-three years after identification of the CFTR gene, controversies still surround the pathogenesis of airways disease, we lack answers to many crucial questions, current treatments are inadequate, and cystic fibrosis (CF) remains a life shortening and too often lethal disease. A major impediment to progress has been lack of a CF animal model other than the mouse. CF mice fail to develop lung disease, the cause of most CF morbidity and mortality. We have now developed pigs with targeted alterations of the CFTR gene. CF pigs spontaneously develop the hallmark features of CF lung disease, including airway infection, inflammation, airway wall remodeling, mucus accumulation, and airway obstruction. Within hours of birth, CF pigs fail to eradicate bacteria as effectively as wild-type pigs. In this Program three senior and highly accomplished investigators will seize the unique opportunity to use CF pigs to answer key questions about CF lung disease. Together, the three projects will discover how loss of CFTR function affects: a) mucociliary transport;b) the response of airways to viral infection;c) HCO3- secretion and control of airway surface liquid pH;and d) bacterial killing on the airway surface. The Project Leaders have an outstanding track record of collaboration in CF, and here they sharpen their focus to a common goal. Their research is highly creative and is supported by five cores that provide innovative services and infrastructure. Discoveries from this PPG will accelerate development of novel therapies for patients who suffer from this devastating disease.
The three projects will discover how loss of CFTR function affects: a) mucociliary transport;b) the response of airways to viral infection;c) HCOa'secretion and control of airway surface liquid pH;and d) bacterial killing on the airway surface.
|Cook, Daniel P; Adam, Ryan J; Zarei, Keyan et al. (2017) CF airway smooth muscle transcriptome reveals a role for PYK2. JCI Insight 2:|
|Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher et al. (2017) Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. Am J Respir Crit Care Med 195:1617-1628|
|Meyerholz, David K; Reznikov, Leah R (2017) Simple and reproducible approaches for the collection of select porcine ganglia. J Neurosci Methods 289:93-98|
|Sinn, P L; Hwang, B-Y; Li, N et al. (2017) Novel GP64 envelope variants for improved delivery to human airway epithelial cells. Gene Ther 24:674-679|
|Paemka, Lily; McCullagh, Brian N; Abou Alaiwa, Mahmoud H et al. (2017) Monocyte derived macrophages from CF pigs exhibit increased inflammatory responses at birth. J Cyst Fibros 16:471-474|
|Meyerholz, David K; Ofori-Amanfo, Georgina K; Leidinger, Mariah R et al. (2017) Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models. J Histochem Cytochem 65:607-618|
|Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J et al. (2017) Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs. Crit Care Med 45:e1240-e1246|
|Ramsey, Bonnie W; Welsh, Michael J (2017) AJRCCM: 100-Year Anniversary. Progress along the Pathway of Discovery Leading to Treatment and Cure of Cystic Fibrosis. Am J Respir Crit Care Med 195:1092-1099|
|Vargas Buonfiglio, Luis G; Mudunkotuwa, Imali A; Abou Alaiwa, Mahmoud H et al. (2017) Effects of Coal Fly Ash Particulate Matter on the Antimicrobial Activity of Airway Surface Liquid. Environ Health Perspect 125:077003|
|Cooney, Ashley L; Abou Alaiwa, Mahmoud H; Shah, Viral S et al. (2016) Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight 1:|
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