PPG - Gene Therapy for Cystic Fibrosis Lung Disease

Summary

Principal Investigator: Paul B McCray
Abstract: Gene transfer to the airways of patients with cystic fibrosis (CF) could represent a treatment breakthrough. However, nineteen years after the identification of the CFTR gene, we still lack new therapies based on advancements in our understanding of the genetic basis of CF. While the principles of gene transfer are sound and have been demonstrated in cell culture and animal models, the promise of the approach has not yet been translated into "gene therapy" for CF. One reason for this delay has been the absence of an animal model that mimics the disease in which to test novel therapies. To overcome this bottleneck, the investigators of this PPG recently developed a new model of the disease by disrupting CFTR gene function in pigs, whose lungs resemble those of humans. This remarkable model exhibits features of CF in humans, including meconium ileus, pancreatic insufficiency, liver and gall bladder disease, and absence of CFTR anion transport in nasal and tracheal epithelia. Early signs in the longestlived animal suggest the spontaneous development of pulmonary inflammation and infection. In this Program, four senior and highly accomplished investigators will seize this unique opportunity and use CFTR-/- and CFTR AF508/AF508 pigs to study gene based therapies for lung disease. Project 1 focuses on the use of lentiviral vectors with envelopes that target the apical surface of epithelia to attain persistent expression of CFTR. They will develop an optimal lentiviral envelope for gene transfer to pig epithelia and test this in the CFTR AF508/AF508 model. Project 2 will use directed evolution of AAV vectors to develop more efficient AAV capsids for targeting the epithelial cells of the airways. They will then use these novel tools to transduce ain/vay epithelia and express CFTR with a goal of preventing or delaying the onset of pulmonary manifestations of CF in a pig model. Project 3 will continue to develop the CF pig model to address key issues including: correction of meconium ileus, the identification of modifier genes of the CF phenotype, and investigating the timing of CFTR expression needed to have a therapeutic effect. Project 4 will develop targeted RNA interference (RNAi) as a therapeutic tool for CF. Proof of principle studies will target the chemokine IL-8 using both viral and non-viral delivery approaches. The Project Leaders have an outstanding track record of collaboration in CF, and here they are focused on a common goal. Their research is highly creative and is supported by four cores that provide innovative services and key infrastructure. The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease.
Funding Period: 1997-09-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc A novel gene delivery method transduces porcine pancreatic duct epithelial cells
    M A Griffin
    Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
    Gene Ther 21:123-30. 2014
  2. pmc Pancreatic damage in fetal and newborn cystic fibrosis pigs involves the activation of inflammatory and remodeling pathways
    Maisam Abu-El-Haija
    Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
    Am J Pathol 181:499-507. 2012
  3. pmc Advances in cell and gene-based therapies for cystic fibrosis lung disease
    Mayumi Oakland
    Department of Microbiology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA
    Mol Ther 20:1108-15. 2012
  4. pmc Pancreatic and biliary secretion are both altered in cystic fibrosis pigs
    Aliye Uc
    Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
    Am J Physiol Gastrointest Liver Physiol 303:G961-8. 2012
  5. pmc Computer-aided analysis of airway trees in micro-CT scans of ex vivo porcine lung tissue
    Christian Bauer
    Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, IA 52242, USA
    Comput Med Imaging Graph 36:601-9. 2012
  6. pmc Sinus hypoplasia precedes sinus infection in a porcine model of cystic fibrosis
    Eugene H Chang
    Department of Otolaryngology Head and Neck Surgery, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Laryngoscope 122:1898-905. 2012
  7. pmc A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator
    Shyam Ramachandran
    Department of Pediatrics, Interdisciplinary Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 109:13362-7. 2012
  8. pmc Do cell junction protein mutations cause an airway phenotype in mice or humans?
    Eugene H Chang
    Department of Otolaryngology Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, USA
    Am J Respir Cell Mol Biol 45:202-20. 2011
  9. pmc Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice
    Lynda S Ostedgaard
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 108:2921-6. 2011
  10. pmc Enamel pathology resulting from loss of function in the cystic fibrosis transmembrane conductance regulator in a porcine animal model
    Eugene H Chang
    Department of Otolaryngology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Cells Tissues Organs 194:249-54. 2011

Research Grants

Detail Information

Publications75

  1. pmc A novel gene delivery method transduces porcine pancreatic duct epithelial cells
    M A Griffin
    Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
    Gene Ther 21:123-30. 2014
    ..The celiac artery can be accessed via the umbilical artery in newborns and via the femoral artery at older ages--delivery approaches that can be translated to humans...
  2. pmc Pancreatic damage in fetal and newborn cystic fibrosis pigs involves the activation of inflammatory and remodeling pathways
    Maisam Abu-El-Haija
    Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
    Am J Pathol 181:499-507. 2012
    ..Proinflammatory, complement cascade, proapoptotic, and profibrotic pathways are activated in CF pig pancreas, and likely contribute to the destructive process...
  3. pmc Advances in cell and gene-based therapies for cystic fibrosis lung disease
    Mayumi Oakland
    Department of Microbiology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA
    Mol Ther 20:1108-15. 2012
    ..This review discusses current challenges and advancements in viral and nonviral vectors, cell-based therapies, and CF animal models...
  4. pmc Pancreatic and biliary secretion are both altered in cystic fibrosis pigs
    Aliye Uc
    Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
    Am J Physiol Gastrointest Liver Physiol 303:G961-8. 2012
    ..These results indicate that pancreatic and biliary secretions are altered in CF pigs. Abnormal pancreatic and biliary secretion in CF may have important implications in disease pathogenesis...
  5. pmc Computer-aided analysis of airway trees in micro-CT scans of ex vivo porcine lung tissue
    Christian Bauer
    Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, IA 52242, USA
    Comput Med Imaging Graph 36:601-9. 2012
    ..No false positive airway branches were found. A detailed performance analysis for different airway tree hierarchy levels, lung inflation levels and piglets with/without cystic fibrosis is presented in the paper...
  6. pmc Sinus hypoplasia precedes sinus infection in a porcine model of cystic fibrosis
    Eugene H Chang
    Department of Otolaryngology Head and Neck Surgery, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Laryngoscope 122:1898-905. 2012
    ..Our objective was to study the early pathogenesis of sinus disease in CF...
  7. pmc A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator
    Shyam Ramachandran
    Department of Pediatrics, Interdisciplinary Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 109:13362-7. 2012
    ..This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation...
  8. pmc Do cell junction protein mutations cause an airway phenotype in mice or humans?
    Eugene H Chang
    Department of Otolaryngology Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, USA
    Am J Respir Cell Mol Biol 45:202-20. 2011
    ..Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described...
  9. pmc Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice
    Lynda S Ostedgaard
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 108:2921-6. 2011
    ..These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRΔR may have utility for AAV-mediated gene transfer in CF...
  10. pmc Enamel pathology resulting from loss of function in the cystic fibrosis transmembrane conductance regulator in a porcine animal model
    Eugene H Chang
    Department of Otolaryngology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Cells Tissues Organs 194:249-54. 2011
    ..The enamel of newborn CFTR-null and CFTR-ΔF508 animals is hypomineralized. Together, these data provide a molecular basis for interpreting enamel disease associated with disruptions to CFTR and AE2 expression...
  11. pmc Defective fluid secretion from submucosal glands of nasal turbinates from CFTR-/- and CFTR (ΔF508/ΔF508) pigs
    Hyung Ju Cho
    Cystic Fibrosis Research Laboratory, Psychology Department, Stanford University, Stanford, California, United States of America
    PLoS ONE 6:e24424. 2011
    ..We asked if glands from pig nasal turbinates have secretory responses similar to those of tracheal glands and if CF nasal glands show reduced fluid secretion...
  12. ncbi Current prospects for RNA interference-based therapies
    Beverly L Davidson
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Nat Rev Genet 12:329-40. 2011
    ..Here we describe the broad range of approaches to achieve targeted gene silencing for therapy, discuss important considerations when developing RNAi triggers for use in humans, and review the current status of clinical trials...
  13. pmc The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs
    Lynda S Ostedgaard
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Sci Transl Med 3:74ra24. 2011
    ..These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics...
  14. pmc Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions
    Daniel Lorentzen
    Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
    Free Radic Biol Med 50:1144-50. 2011
    ..The correlation between lung function and SCN(-) concentration in CF patients may reflect a beneficial role for SCN(-)...
  15. pmc Enhanced sialic acid-dependent endocytosis explains the increased efficiency of infection of airway epithelia by a novel adeno-associated virus
    David D Dickey
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Virol 85:9023-30. 2011
    ..Thus, sialic acid serves as not just an attachment factor but is also required for AAV2.5T internalization, possibly representing an important rate-limiting step for other viruses that use sialic acids...
  16. pmc Genetic therapies for cystic fibrosis lung disease
    Patrick L Sinn
    Program in Gene Therapy, Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
    Hum Mol Genet 20:R79-86. 2011
    ..Here, we review recent developments that are advancing this field of investigation...
  17. ncbi Safety assessment of nebulized xylitol in beagle dogs
    Matthew D Reed
    Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA
    Inhal Toxicol 24:365-72. 2012
    ..The No Observed Effect Level was the high-exposure level and suggests that inhaled xylitol is safe for clinical administration...
  18. pmc Transcriptional targeting in the airway using novel gene regulatory elements
    Erin R Burnight
    Interdisciplinary Graduate Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, 52242, USA
    Am J Respir Cell Mol Biol 47:227-33. 2012
    ..These results will guide the development of optimal vectors for sufficient, sustained CFTR expression in airway epithelia...
  19. pmc Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect
    Qian Dong
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 109:917-22. 2012
    ..Because no one modification corrected both maturation and gating, perhaps more than a single agent will be required to correct all CFTR-ΔF508 defects...
  20. pmc Chemosensory functions for pulmonary neuroendocrine cells
    Xiaoling Gu
    1 Department of Biology, Washington University in St Louis, Missouri
    Am J Respir Cell Mol Biol 50:637-46. 2014
    ..Together, these data indicate that human airway epithelia harbor specialized cells that respond to volatile chemical stimuli, and may help to explain clinical observations of odorant-induced airway reactions. ..
  21. pmc Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs
    Mark J Hoegger
    Departments of Molecular Physiology and Biophysics, Internal Medicine, Pediatrics, Radiology, and Biomedical Engineering, and Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242
    Proc Natl Acad Sci U S A 111:2355-60. 2014
    ..The increased granularity of MCT data provided by this assay may provide an opportunity to better understand host defense mechanisms and the pathogenesis of airway disease. ..
  22. ncbi Effects of airway surface liquid pH on host defense in cystic fibrosis
    Abigail R Berkebile
    Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Int J Biochem Cell Biol 52:124-9. 2014
    ..Understanding how changes in pH impact mucosal immunity may lead to new therapies that can modify the airway surface liquid environment, improve airway defenses, and alter the disease course...
  23. pmc Neonates with cystic fibrosis have a reduced nasal liquid pH; a small pilot study
    Mahmoud H Abou Alaiwa
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    J Cyst Fibros 13:373-7. 2014
    ..Disrupted HCO3(-) transport and reduced airway surface liquid (ASL) pH in cystic fibrosis (CF) may initiate airway disease. We hypothesized that ASL pH is reduced in neonates with CF...
  24. pmc Early airway structural changes in cystic fibrosis pigs as a determinant of particle distribution and deposition
    Maged Awadalla
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, C33GH, Iowa City, IA, 52242, USA
    Ann Biomed Eng 42:915-27. 2014
    ..The irregular particle distribution and increased deposition in newborn CF pig airways suggest that early airway structural abnormalities might contribute to CF disease pathogenesis. ..
  25. pmc Air trapping and airflow obstruction in newborn cystic fibrosis piglets
    Ryan J Adam
    1 Department of Internal Medicine
    Am J Respir Crit Care Med 188:1434-41. 2013
    ..Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus buildup...
  26. pmc ATP and AMP mutually influence their interaction with the ATP-binding cassette (ABC) adenylate kinase cystic fibrosis transmembrane conductance regulator (CFTR) at separate binding sites
    Christoph O Randak
    From the Departments of Pediatrics
    J Biol Chem 288:27692-701. 2013
    ..They further indicate that the active center of the adenylate kinase comprises ATP-binding site 2. ..
  27. pmc Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs
    Shyam Ramachandran
    1 Department of Pediatrics
    Am J Respir Cell Mol Biol 49:544-51. 2013
    ..Thus, miR-509-3p and miR-494 are dynamic regulators of CFTR abundance and function in normal, non-CF airway epithelia...
  28. pmc Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs
    David A Stoltz
    Department of Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa 52242, USA
    J Clin Invest 123:2685-93. 2013
    ..This model may be of value for understanding CF pathophysiology and testing new preventions and therapies...
  29. pmc Principles for valid histopathologic scoring in research
    K N Gibson-Corley
    Carver College of Medicine, University of Iowa, 500 Newton Rd, 1165ML, Iowa City, IA 52242, USA Email
    Vet Pathol 50:1007-15. 2013
    ..Understanding key principles of tissue scoring can help in the development and/or optimization of scoring systems so as to consistently yield meaningful and valid scoring data. ..
  30. pmc Adenoviral gene transfer corrects the ion transport defect in the sinus epithelia of a porcine CF model
    Andrea E Potash
    Department of Otolaryngology Head and Neck Surgery, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Mol Ther 21:947-53. 2013
    ..These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis...
  31. pmc Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung
    Alejandro A Pezzulo
    Department of Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Nature 487:109-13. 2012
    ..These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions...
  32. pmc CFTR is required for maximal transepithelial liquid transport in pig alveolar epithelia
    Xiaopeng Li
    Department of Internal Medicine, University of Iowa, Iowa City, USA
    Am J Physiol Lung Cell Mol Physiol 303:L152-60. 2012
    ..These insights may help to develop new treatment strategies for pulmonary edema and respiratory distress syndrome, diseases in which lung liquid transport is disrupted...
  33. pmc Requirements for ion and solute transport, and pH regulation during enamel maturation
    Rodrigo S Lacruz
    Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California 90033, USA
    J Cell Physiol 227:1776-85. 2012
    ....
  34. pmc Demonstration of phosphoryl group transfer indicates that the ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) exhibits adenylate kinase activity
    Christoph O Randak
    Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA
    J Biol Chem 287:36105-10. 2012
    ..These biochemical data complement earlier biophysical studies of CFTR and indicate that the ABC transporter CFTR can function as an adenylate kinase...
  35. pmc Human cystic fibrosis airway epithelia have reduced Cl- conductance but not increased Na+ conductance
    Omar A Itani
    Department of Internal Medicine, The Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 108:10260-5. 2011
    ..These results indicate that Na(+) conductance was not increased in these cultured CF tracheal/bronchial epithelia and point to loss of anion transport as key to airway epithelial dysfunction in CF...
  36. pmc Genetic modifications of pigs for medicine and agriculture
    Jeffrey J Whyte
    National Swine Resource and Research Center, University of Missouri, Columbia, Missouri 65211, USA
    Mol Reprod Dev 78:879-91. 2011
    ..Improvements in both methods of gene alteration and efficiency of model animal production are key to enabling routine use of these swine models in medicine and agriculture...
  37. pmc Glucose depletion in the airway surface liquid is essential for sterility of the airways
    Alejandro A Pezzulo
    Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America
    PLoS ONE 6:e16166. 2011
    ..This mechanism is important for sterility of the airways and has implications in hyperglycemia and conditions that result in disruption of the epithelial barrier in the lung...
  38. pmc A mutation in CFTR modifies the effects of the adenylate kinase inhibitor Ap5A on channel gating
    Qian Dong
    Departments of Internal Medicine and Molecular Physiology and Biophysics, Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Biophys J 95:5178-85. 2008
    ..These results also suggest that a better understanding of the adenylate kinase activity of CFTR may be of value in developing new therapeutic strategies for cystic fibrosis...
  39. pmc Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer
    Christopher S Rogers
    Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
    J Clin Invest 118:1571-7. 2008
    ..In addition, because gene-modified mice often fail to replicate human diseases, this approach could be used to generate models of other human genetic diseases in species other than mice...
  40. pmc Lentivirus vector can be readministered to nasal epithelia without blocking immune responses
    Patrick L Sinn
    Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA
    J Virol 82:10684-92. 2008
    ..Prolonged gene expression has been observed in vivo following a single dose of virus vector; however, depending on the application, repeated administration of vector may be necessary to achieve stable, therapeutic gene expression...
  41. pmc Basolateral entry and release of New and Old World arenaviruses from human airway epithelia
    Douglas E Dylla
    The Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Virol 82:6034-8. 2008
    ..Viral egress from infected epithelia exhibited basolateral polarity. This study demonstrates that respiratory entry of arenaviruses occurs via basolateral receptors...
  42. pmc Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia
    Alok S Shah
    Departments of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 105:3380-5. 2008
    ..These results emphasize the role of BBS proteins in both the structure and function of motile cilia. They also invite additional scrutiny of motile cilia dysfunction in patients with this disease...
  43. pmc The porcine lung as a potential model for cystic fibrosis
    Christopher S Rogers
    Department of Internal Medicine, Roy J Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Am J Physiol Lung Cell Mol Physiol 295:L240-63. 2008
    ..Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF...
  44. ncbi Nuclear remodeling and nuclear reprogramming for making transgenic pigs by nuclear transfer
    Randall S Prather
    Division of Animal Science, Food for the 21st Century, College of Food, Agriculture and Natural Resources, University of Missouri Columbia, 920 East Campus Drive, E125 ASRC, Columbia, Missouri 65211 5300, USA
    Adv Exp Med Biol 591:1-13. 2007
    ..However, even with the current low efficiencies this technique has proved very valuable for the production of animals that might be useful for tissue or organ transplantation to humans...
  45. pmc Functional effects of coxsackievirus and adenovirus receptor glycosylation on homophilic adhesion and adenoviral infection
    Katherine J D Ashbourne Excoffon
    Department of Internal Medicine, University of Iowa, 440 EMRB, Iowa City, IA 52242, USA
    J Virol 81:5573-8. 2007
    ..These data have important implications for both cancers with altered glycosylation states and cancer treatments using oncolytic adenovirus...
  46. pmc Processing and function of CFTR-DeltaF508 are species-dependent
    Lynda S Ostedgaard
    Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 104:15370-5. 2007
    ....
  47. pmc Targeted genetic modification: xenotransplantation and beyond
    Randall S Prather
    Division of Animal Science, University of Missouri Columbia, Columbia, Missouri 65211 5300, USA
    Cloning Stem Cells 9:17-20. 2007
  48. ncbi Enhanced gene expression conferred by stepwise modification of a nonprimate lentiviral vector
    Patrick L Sinn
    Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Hum Gene Ther 18:1244-52. 2007
    ..These sequential modifications provide an improved FIV lentivirus platform for gene therapy applications and may be applied to other retroviral vectors...
  49. pmc Vaccinia virus entry, exit, and interaction with differentiated human airway epithelia
    Paola D Vermeer
    Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, 500 EMRB, Iowa City, IA 52242, USA
    J Virol 81:9891-9. 2007
    ....
  50. pmc Concentration and composition of free amino acids and osmolalities of porcine oviductal and uterine fluid and their effects on development of porcine IVF embryos
    Rongfeng Li
    Division of Animal Science, University of Missouri Columbia, Columbia, Missouri 65211, USA
    Mol Reprod Dev 74:1228-35. 2007
    ..When the embryos were cultured in PZM3-SAA at 330 mOsM for the first 72 hr and then transferred to 250 mOsM (33.3 +/- 3.4%), the blastocyst rate was higher than original PZM3 (21.2 +/- 2.2%) (288 mOsM)...
  51. ncbi Basolateral chloride current in human airway epithelia
    Omar A Itani
    Howard Hughes Medical Institute, Univ of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Lung Cell Mol Physiol 293:L991-9. 2007
    ..Its regulation by cAMP and PKC signaling pathways suggests that coordinated regulation of Cl(-) conductance in both apical and basolateral membranes may be important in controlling transepithelial Cl(-) movement...
  52. ncbi The Coxsackievirus and Adenovirus Receptor: a new adhesion protein in cochlear development
    Katherine J D A Excoffon
    Department of Internal Medicine, Division of Pulmonary Medicine, University of Iowa, 440 EMRB, Iowa City, IA 52242, USA
    Hear Res 215:1-9. 2006
    ....
  53. ncbi Cloned transgenic swine via in vitro production and cryopreservation
    Rongfeng Li
    Division of Animal Science, University of Missouri Columbia, Columbia, Missouri 65211, USA
    Biol Reprod 75:226-30. 2006
    ..Application of this technique may permit national and international movement of cloned transgenic swine embryos, storage until a suitable surrogate is available, or the long-term frozen storage of valuable genetics...
  54. ncbi Genetically modified pigs for medicine and agriculture
    Randall S Prather
    Division of Animal Science, University of Missouri, Columbia, MO 6521, USA
    Biotechnol Genet Eng Rev 25:245-65. 2008
    ..Additional types of genetic modifications will likely provide animals with characteristics that will benefit humans in currently unimagined ways...
  55. pmc Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed
    Vincent H J Leonard
    Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
    J Clin Invest 118:2448-58. 2008
    ..Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV...
  56. pmc Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs
    Christopher S Rogers
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Science 321:1837-41. 2008
    ..The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment...
  57. ncbi Somatic cell nuclear transfer efficiency: how can it be improved through nuclear remodeling and reprogramming?
    Kristin M Whitworth
    Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211, USA
    Mol Reprod Dev 77:1001-15. 2010
    ..Finally we will briefly touch on other aspects of SCNT that may improve the development of cloned embryos...
  58. pmc Pathology of gastrointestinal organs in a porcine model of cystic fibrosis
    David K Meyerholz
    Department of Pathology, Howard Hughes Medical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Am J Pathol 176:1377-89. 2010
    ..Thus, mucus cell hyperplasia and mucus accumulation play prominent roles in early disease. Our findings also have implications for CF lung disease, and they lay the foundation for a better understanding of CF pathogenesis...
  59. pmc Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs
    Nam Soo Joo
    Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California 94305 2130, USA
    J Clin Invest 120:3161-6. 2010
    ..These data are a step toward determining whether gland secretory defects contribute to CF airway disease...
  60. pmc Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia
    Jeng Haur Chen
    Department of Internal Medicine, University of Iowa, Iowa City, 52242, USA
    Cell 143:911-23. 2010
    ..These results indicate that CFTR provides the predominant transcellular pathway for Cl⁻ and HCO₃⁻ in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease...
  61. pmc Isoform-specific regulation and localization of the coxsackie and adenovirus receptor in human airway epithelia
    Katherine J D A Excoffon
    Department of Biological Sciences, Wright State University, Dayton, Ohio, United States of America
    PLoS ONE 5:e9909. 2010
    ..In summary, apical localization of CAR(Ex8) may be responsible for initiation of respiratory adenoviral infections and this localization appears to be regulated by interactions with PDZ-domain containing proteins...
  62. pmc cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways
    Robert J Lee
    Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6085, USA
    J Clin Invest 120:3137-48. 2010
    ..These results identify important molecular mechanisms of cAMP-dependent secretion, including a requirement for Ca2+ signaling, and suggest new therapeutic approaches to correct defective submucosal gland secretion in CF...
  63. pmc Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth
    David A Stoltz
    Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Sci Transl Med 2:29ra31. 2010
    ....
  64. pmc Loss of cystic fibrosis transmembrane conductance regulator function produces abnormalities in tracheal development in neonatal pigs and young children
    David K Meyerholz
    Department of Pathology, University of Iowa, Iowa City, 52242, USA
    Am J Respir Crit Care Med 182:1251-61. 2010
    ..Although airway abnormalities are common in patients with cystic fibrosis (CF), it is unknown whether they are all secondary to postnatal infection and inflammation, which characterize the disease...
  65. pmc The piglet as a model for B cell and immune system development
    J E Butler
    Department of Microbiology, University of Iowa, Iowa City, IA, United States
    Vet Immunol Immunopathol 128:147-70. 2009
    ..This review summarizes the history of the development of the piglet as a model for antibody repertoire development, thus providing a framework to guide future investigators...
  66. pmc Acute regulation of tight junction ion selectivity in human airway epithelia
    Andrea N Flynn
    Howard Hughes Medical Institute, Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 106:3591-6. 2009
    ..Such regulation could facilitate coupling of the passive flow of counter ions to active transcellular transport, thereby controlling net transepithelial salt and water transport...
  67. pmc Motile cilia of human airway epithelia are chemosensory
    Alok S Shah
    Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
    Science 325:1131-4. 2009
    ..Hence, like primary cilia, classical motile cilia also contain sensors to detect the external environment...
  68. pmc Directed evolution of adeno-associated virus to an infectious respiratory virus
    Katherine J D A Excoffon
    Department of Internal Medicine, University of Iowa, 440 EMRB, Iowa City, IA 52241, USA
    Proc Natl Acad Sci U S A 106:3865-70. 2009
    ..Thus, under appropriate selective pressures, viruses can evolve to be more infectious than observed in nature, a finding that holds significant implications for designing vectors for gene therapy and for understanding emerging pathogens...
  69. pmc Differential gene expression in human conducting airway surface epithelia and submucosal glands
    Anthony J Fischer
    Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
    Am J Respir Cell Mol Biol 40:189-99. 2009
    ..This study illustrates the power of LCM in defining the roles of specific anatomic features in airway biology and may be useful in examining how disease states alter transcriptional programs in the conducting airways...
  70. pmc Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits
    Xiang ming Zha
    Howard Hughes Medical Institute and Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 106:3573-8. 2009
    ..They also suggest a mechanism by which the redox state can dynamically regulate membrane protein activity by forming intracellular bridges...
  71. pmc ASIC2 subunits target acid-sensing ion channels to the synapse via an association with PSD-95
    Xiang ming Zha
    Howard Hughes Medical Institute, Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Neurosci 29:8438-46. 2009
    ..These results indicate that ASIC2 facilitates ASIC1a localization and function in dendritic spines and suggest that the two subunits work in concert to regulate neuronal function...
  72. pmc Reovirus preferentially infects the basolateral surface and is released from the apical surface of polarized human respiratory epithelial cells
    Katherine J D A Excoffon
    Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
    J Infect Dis 197:1189-97. 2008
    ..These results establish the existence of an infectious circuit for reovirus in polarized human respiratory epithelial cells...
  73. pmc Integration site choice of a feline immunodeficiency virus vector
    Yubin Kang
    Program in Gene Therapy, Department of Pediatrics, University of Iowa, Iowa City, 52242, 52242, USA
    J Virol 80:8820-3. 2006
    ..FIV integration preferences are more similar to those of primate lentiviruses and distinct from those of Moloney murine leukemia virus, avian sarcoma leukosis virus, and foamy virus...

Research Grants30

  1. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  4. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  5. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  6. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  7. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  8. Endothelial Barrier Protection and Repair in Acute Lung Injury
    Stephen M Black; Fiscal Year: 2013
    ..abstract_text> ..
  9. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  10. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  11. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  12. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  13. GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS
    William B Guggino; Fiscal Year: 2013
    ..Project IV will focus on the Biology of AAV. Finally, there are three cores, an Expression, a Vector Core, and an Administration Core. ..