Modulation of Genes Responsible for Cilia Length by Exposure to Cigarette Smoke

Summary

Principal Investigator: Ann E Tilley
Abstract: DESCRIPTION (provided by applicant): Candidate. I am an Assistant Professor of Genetic Medicine and of Medicine, Division of Pulmonary and Critical Care Medicine, at Weill Cornell Medical College. I have been working in Dr. Ronald G. Crystal's lab since my fellowship, focused on evaluation of gene expression in the airway epithelium in healthy nonsmokers, smokers, and smokers with COPD. For the last two years I have taken courses leading to a Master's in Clinical Investigation degree to gain formal instruction relevant to a career in patient-oriented research. I am seeking the K23 award to gain the mentored, practical experience that I need to attain my long-term goal of being an independent investigator in the field of smoking-related lung disease. Environment. My primary mentor for the proposal is Dr. Ronald G. Crystal. Dr. Crystal has an outstanding record of mentoring young investigators to independent careers, and has sufficient funding to provide resources for my proposed project. Co-mentors are Dr. Andrew Clark, providing expertise in biostatistics and bioinformatics, and Dr. Neil Hackett, providing expertise in molecular biology and the basic science approaches used in the project. Consultants are Dr. Jason Mezey for additional statistics expertise and Dr. Charleen Hollman who will provide guidance related to the conduct of patient-oriented research. Through a combination of structured tutorials, mentorship committee meetings, informal interactions and relevant didactic coursework, I will gain the additional training I need to succeed as an independent investigator. Research. Cigarette smoking is the major risk factor for the development of chronic obstructive pulmonary disease (COPD). One manifestation of COPD is diminished mucociliary clearance, the process by which motile cilia on the surface of the airway epithelium function to sweep mucus and debris in a cephalad direction to clear the airways. Even before the development of COPD, individuals who smoke may demonstrate a reduction in mucociliary clearance. Diminishment in mucociliary clearance leads to mucus plugging, forming a nidus for infection and eventually worsening airway obstruction. We have observed that clinically healthy smokers, who have no signs or symptoms of lung disease and who have normal pulmonary function tests, have cilia that are an average of 10% shorter than the cilia of normal nonsmokers. This decrease in length is likely to have adverse consequences for mucociliary clearance. We hypothesize that the stress of smoking modulates the airway epithelial expression of genes critical to the formation and maintenance of cilia of normal length. We will use bronchoscopy to obtain airway epithelial cells and will study gene expression in those cells both ex vivo and after culture at air-liquid interface, with and without exposure to cigarette smoke. Preliminary data suggests smoking- induced alterations in expression of 6 genes likely to play a role in the growth and maintenance of normal-length cilia. In this context, the current proposal has 3 specific aims: (1) to evaluate the hypothesis that exposure to cigarette smoke will result in shorter cilia in human airway epithelial cells grown in culture at air-liquid interface;(2) to evaluate the hypothesis that in vitro suppression of expression of genes involved in the regulation of ciliogenesis and cilia length will result in short cilia in a culture model;and (3) to evaluate the hypothesis that cigarette smoke exposure induces changes in alternative splicing of ODF2, resulting in dysfunctional cilia formation. An understanding of one of the mechanisms underlying dysfunctional mucociliary clearance in smokers may lead to targets for therapeutic intervention.
Funding Period: 2011-07-12 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers
    Guoqing Wang
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
    BMC Med Genomics 5:21. 2012
  2. pmc High correlation of the response of upper and lower lobe small airway epithelium to smoking
    Ben Gary Harvey
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America
    PLoS ONE 8:e72669. 2013
  3. pmc Intraflagellar transport gene expression associated with short cilia in smoking and COPD
    Justina Hessel
    Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America
    PLoS ONE 9:e85453. 2014
  4. ncbi FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro
    Angelika Brekman
    Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
    Am J Respir Cell Mol Biol 51:688-700. 2014

Research Grants

  1. Mechanisms of COPD Subphenotype Development
    MICHAEL BRADLEY DRUMMOND; Fiscal Year: 2013
  2. Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia
    Lawrence E Ostrowski; Fiscal Year: 2013
  3. HORMONAL INFLUENCES ON AIRWAY DISEASE
    Raksha Jain; Fiscal Year: 2013
  4. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  5. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
  7. COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function
    Ronald G Crystal; Fiscal Year: 2013
  8. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
  9. Epigenetic Changes Link COPD and Lung Cancer
    Yohannes Tesfaigzi; Fiscal Year: 2013
  10. Spinal Cord Injury, Plasticity and Transplant Mediated Repair
    John D Houle; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers
    Guoqing Wang
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
    BMC Med Genomics 5:21. 2012
    ....
  2. pmc High correlation of the response of upper and lower lobe small airway epithelium to smoking
    Ben Gary Harvey
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America
    PLoS ONE 8:e72669. 2013
    ....
  3. pmc Intraflagellar transport gene expression associated with short cilia in smoking and COPD
    Justina Hessel
    Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America
    PLoS ONE 9:e85453. 2014
    ..Strategies to normalize cilia length may be an important avenue for novel COPD therapies. ..
  4. ncbi FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro
    Angelika Brekman
    Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
    Am J Respir Cell Mol Biol 51:688-700. 2014
    ....

Research Grants30

  1. Mechanisms of COPD Subphenotype Development
    MICHAEL BRADLEY DRUMMOND; Fiscal Year: 2013
    ..In addition, each member of the mentoring committee serves as an excellent role model for the applicant's career development into an independent investigator. ..
  2. Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia
    Lawrence E Ostrowski; Fiscal Year: 2013
    ....
  3. HORMONAL INFLUENCES ON AIRWAY DISEASE
    Raksha Jain; Fiscal Year: 2013
    ..These findings could lead to novel therapeutic approaches involving inhaled hormone manipulation in patients with bronchiectasis and other airway diseases such as asthma and chronic obstructive pulmonary disease. ..
  4. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  5. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  7. COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function
    Ronald G Crystal; Fiscal Year: 2013
    ..abstract_text> ..
  8. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  9. Epigenetic Changes Link COPD and Lung Cancer
    Yohannes Tesfaigzi; Fiscal Year: 2013
    ..Together, the integrated results from these studies will provide novel insights into mechanisms that connect COPD to the development of lung cancer. ..
  10. Spinal Cord Injury, Plasticity and Transplant Mediated Repair
    John D Houle; Fiscal Year: 2013
    ..This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI. ..
  11. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  12. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  13. Quantitative Structural and Functional Imaging of the Lung
    Rahim R Rizi; Fiscal Year: 2013
    ..These novel markers will significantly improve understanding of COPD and will be critical to characterizing disease response to therapy. ..