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.

Public Health Relevance

Project Narrative One of the ways in which smoking leads to lung disease is by causing is dysfunction of cilia, the hair-like projections on cells lining the airways of the lungs, that function to sweep pathogens and debris out of the lung. We have found that the respiratory cilia of smokers are approximately 10% shorter than those of nonsmokers, which likely has consequences for ciliary function. We propose to study the genetic mechanisms involved in control of cilia length, which could potentially lead to discovering novel drug targets for smoking-related lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (F1))
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Rothgeb, Ann E
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Tilley, Ann E; Staudt, Michelle R; Salit, Jacqueline et al. (2016) Cigarette Smoking Induces Changes in Airway Epithelial Expression of Genes Associated with Monogenic Lung Disorders. Am J Respir Crit Care Med 193:215-7
Tilley, Ann E; Walters, Matthew S; Shaykhiev, Renat et al. (2015) Cilia dysfunction in lung disease. Annu Rev Physiol 77:379-406
Wang, Guoqing; Wang, Rui; Strulovici-Barel, Yael et al. (2015) Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation. PLoS One 10:e0120824
Staudt, Michelle R; Buro-Auriemma, Lauren J; Walters, Matthew S et al. (2014) Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 190:955-8
Hessel, Justina; Heldrich, Jonna; Fuller, Jennifer et al. (2014) Intraflagellar transport gene expression associated with short cilia in smoking and COPD. PLoS One 9:e85453
Brekman, Angelika; Walters, Matthew S; Tilley, Ann E et al. (2014) FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am J Respir Cell Mol Biol 51:688-700
Walters, Matthew S; De, Bishnu P; Salit, Jacqueline et al. (2014) Smoking accelerates aging of the small airway epithelium. Respir Res 15:94
Harvey, Ben-Gary; Strulovici-Barel, Yael; Vincent, Thomas L et al. (2013) High correlation of the response of upper and lower lobe small airway epithelium to smoking. PLoS One 8:e72669
Wang, Guoqing; Xu, Zhibo; Wang, Rui et al. (2012) Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers. BMC Med Genomics 5:21