The overall goal of this Mentored Clinical Scientist Research Career Development Award proposal is to assist in establishing the independent research career of the candidate in the study of virus-host cell interactions, specifically of the cellular processes contributing to vocal cord dysfunction and upper airway obstruction caused by human papillomavirus (HPV) infections that lead to recurrent respiratory papillomatosis (RRP). The candidate is a board-certified otolaryngology surgeon with a focus on the management of voice disorders and difficult airways. Besides his clinical residency in otolaryngology, the candidate received postdoctoral training in the molecular biology of genus beta HPVs and the mechanisms by which they induce cell proliferation and block apoptosis after DNA damage - issues similar to those to be studied in the research component of this project, focused on the RPP-related genus alpha HPVs. The training and research components of the project are under the supervision of the co-mentors, Dr. Stephen Tyring and Dr. Thomas Albrecht. In addition to the mentored research component, the training plan calls for didactic coursework in such areas as virology, biostatistics, scientific writing, and several aspects of the responsible conduct of research, as well as attending relevant local and national meetings. The research project focuses on elucidating the mechanisms by which RPP-related HPVs block apoptosis and induce cellular proliferation in human keratinocytes. In high-risk HPV infections, the E6 viral protein targets the pro-apoptotic cellular Bak protein (as well as p53) for degradation, and so prevents the normal process of apoptosis from being induced by genotoxic stress. The candidate's preliminary data show that the RRP-related HPVs also retain the ability to target Bak for degradation.
Aim 1 of the research project is to use immunoblotting and shRNA knockdown to determine the ability of HPV6 and HPV11 E6 proteins to blunt the apoptotic response, and also to determine the mechanism for Bak degradation.
Aim 2 is to use a combination of protein pull down assays to identify conserved (Bak, E6AP) and novel binding partners of the 6E6 and 11E6 proteins. Finally, Aim 3 is to use immunostaining techniques to determine the effects of treatments targeted towards the induction of the extrinsic and/or intrinsic apototis pathways in both undifferentiated and differentiated E6-expressing cell cultures. Upon successful completion of this project, there will be a much better understanding of the molecular biology and pathogenic mechanisms of the """"""""low- risk,"""""""" RPP-related HPVs;this information will be invaluable in developing effective, function-sparing treatments for this presently incurable disease process. Further, the candidate will have obtained the preliminary data needed to compete successfully for R01 funding, and the skill set necessary for him to achieve his long-range goal - success as an established, extramurally funded surgeon-scientist focused on effective treatments for RPP and other laryngeal-related diseases.

Public Health Relevance

Recurrent respiratory papillomatosis (RRP) is characterized by the growth of tumors in the upper respiratory tract, caused by infection with the human papilloma virus (HPV). Understanding the effects of HPV6 and HPV11 infection in the airway cells (keratinocytes) will clarify how RRP tumors proliferate in the upper respiratory tract and should lead to the discovery of novel, targeted therapies that can be used for the safe, voice-preserving treatment of this disease. Additionally, principles learned through the molecular study of RRP-associated HPV-host interactions will undoubtedly impact the study and treatment of other virus-induced diseases.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZDC1-SRB-L (45))
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Sklare, Dan
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University of Texas Medical Br Galveston
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United States
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Wang, Jia; Dupuis, Crystal; Tyring, Stephen K et al. (2016) Sterile ? Motif Domain Containing 9 Is a Novel Cellular Interacting Partner to Low-Risk Type Human Papillomavirus E6 Proteins. PLoS One 11:e0149859
Underbrink, Michael P; Dupuis, Crystal; Wang, Jia et al. (2016) E6 proteins from low-risk human papillomavirus types 6 and 11 are able to protect keratinocytes from apoptosis via Bak degradation. J Gen Virol 97:715-24
Rodman, Regina; Mutasa, Simukayi; Dupuis, Crystal et al. (2014) Genetic dysregulation in recurrent respiratory papillomatosis. Laryngoscope 124:E320-5
Venkatesan, Naren N; Pine, Harold S; Underbrink, Michael (2013) Laryngopharyngeal reflux disease in children. Pediatr Clin North Am 60:865-78
Venkatesan, Naren N; Pine, Harold S; Underbrink, Michael P (2012) Recurrent respiratory papillomatosis. Otolaryngol Clin North Am 45:671-94, viii-ix