Human papillomavirus (HPV) causes approximately 5% of all human cancers. While HPV's transforming and tumorigenic properties have been studied extensively in vitro using tissue culture models and in vivo using transgenic animal models that express the HPV oncoproteins, the relevance of these functions in HPV-induced disease have not been verified in a true physiological model. A barrier to understanding HPV oncoprotein function is that HPV cannot infect murine cells, which disallows one from studying HPV disease in laboratory mice. The recent discovery of murine papillomavirus (MmuPV1) provides us the opportunity to study in a preclinical model natural infections and the ability of papillomaviruses to promote neoplastic disease through their oncoproteins, specifically E6 and E7. Using MmuPV1, we have established a mouse model for HPV-induced neoplastic disease in mice allowing us to now define the roles of the E6 and E7 oncoproteins in the context of natural papillomavirus infection. MmuPV1 infects both cutaneous and mucosal epithelia, the later mimicking neoplastic disease caused by the ?high-risk? ?-HPVs. The latter finding is interesting because MmuPV1 E6 and E7 oncoproteins biochemically mimic the ?- and ?-HPVs. We will examine the functions of the MmuPV1 E6 and E7 oncoprotein's in promoting MmuPV1-induced disease, specifically E6's ability to inhibit NOTCH signaling and E7's effects on non-canonical RB function. Using genetically engineered mouse models (GEMMs), we will rigorously test the importance of these functions in promoting skin carcinogenesis using cellular mutations that may complement for these specific functions of E6 and E7. Finally, we will determine if the E6 and E7 oncoproteins from the ?high-risk? ?-HPV, HPV16, can trans-complement for MmuPV1 E6 and E7 oncoproteins using our existing HPV16 transgenic animal models. These studies will further our understanding of the roles E6 and E7 play in promoting papillomavirus-induced disease and could be used to develop novel therapies that target these functions. The main goal of this postdoctoral fellowship is to help me develop the skill sets needed to become a successful faculty member at a research-focused academic institution. The proposed training plan provides me with a unique set of means by which to accomplish this goal including a strong mentoring plan, many opportunities to develop my skills as a mentor and teacher, and an array of career development opportunities including one focused specifically on helping under represented minorities be successful in academia as professors. This combined with the strong training record of my sponsor, Dr. Paul Lambert, and my strong record of productivity as a graduate student are compelling reasons why I should be successful in attaining my career goals. By accomplishing the research goals and training plan, I hope to establish an important niche in the papillomavirus field and to develop the skill sets necessary to establish a successful independent research program as a faculty member in a research-focused academic institution.
Despite the presence of a prophylactic vaccine, human papillomaviruses will continue to cause cancer world- wide, and the lack of a tractable animal model to study HPV-induced pathogenesis and carcinogenesis has prevented efforts geared towards generating new therapies to combat pre-existing papillomavirus-induced disease. This proposal addresses this deficiency and will use a papillomavirus that infects laboratory mice causing skin papillomas and cutaneous squamous cell carcinomas. The experiments proposed in this study will determine the relevance of key cellular pathways subverted by the MmuPV1 oncoproteins E6 and E7 and determine if the E6 and E7 oncoproteins of MmuPV1 have overlapping functions with HPV16 E6 and E7.
