This application requests a mentored career development award for an ophthalmology trained ocular pathologist with a scientific interest in understanding key cellular pathways that can be targeted for therapeutic treatment. The candidate will focus initially on the Src-family kinases (SFKs) and Src-activating and signaling molecule (Srcasm) pathway in ocular surface wound healing and tumorigenesis because of prior studies that have shown its significance and amenability for topical therapeutic strategies in skin keratinocyte wounds and tumors. The candidate will have the following objectives during the award period: 1) development of an individual research program through mentorship, didactics, related workshops, and instruction in responsible conduct of research; 2) refinement of research and management skills by way of mentorship and related activities; 3) enhancement of communication and writing skills by means of presentations, manuscript and grant preparations; 4) and acquisition of future funding by assembling preliminary results and designing experimental aims. By the end of the award period, the candidate will have gained the mentorship, knowledge, and valuable hands-on experience required to design, propose and implement experiments in vision research. The candidate's long-term goal is to lead a research program that strategically addresses significant, critical questions in the field of ophthalmic research with novel, rational approaches. This project will be under the supervision of premier, senior investigators from the Department of Ophthalmology and Dermatology, who will jointly provide guidance in the proposed research and candidate's career development. The exceptional scientific environment at the University of Pennsylvania promotes such collaborative efforts between departments. In addition, there is a strong legacy at the University of Pennsylvania of promoting and developing junior faculty members to positions of leadership. The mentors uphold this tradition personally and in their respective departments. Both the Department of Ophthalmology and Dermatology are leading institutions, ranking in the top tier in NIH grant funding, publications in high impact journals, and training of outstanding physicians and scientists. A comprehensive mentoring plan has been created for the progressive growth and development of the candidate's goals and career. The plan includes regular, scheduled meetings between the mentors and candidate; didactics; workshops; and activities to enhance the candidate's research, management, communication, and writing skills. In addition to their guidance, the mentors will provide the necessary resources, equipment, and expertise to execute the specific aims of the proposal. There are multiple cores and institutions throughout the campus, as well, with state-of-the-art equipment that will help facilitate the execution of the proposed aims. The interactive and spirited scientific community that exists at the University of Pennsylvania will provide numerous opportunities for the candidate to promote the results from the K08 award and advance the candidate's career. Vision loss due to ocular surface disease is the second major cause of blindness worldwide. Although the causes are varied, the most common pathway leading to the loss of vision is scarring of the ocular surface. Therapeutic interventions early in the process of wound healing are critical to addressing this global burden. The SFK/Srcasm pathway appears to regulate cellular proliferation, migration, and differentiation in wound healing, making it amenable to therapeutic approaches. This pathway, however, also plays a significant role in tumorigenesis as well, which is expected given the commonalities between wounds and tumors. The results obtained from studying this pathway in both ocular surface wound healing and tumorigenesis, therefore, will lead to potential therapeutic targets in both disorders. This goal will be accomplished with 3 specific aims as listed below. The institution, mentors, and collaborators outlined in this proposal are dedicated to research and cultivating the careers of early investigators. This structured career development plan will position the candidate for independence at the end of the award period.
AIM 1) Determine the effect of SFKs on corneal epithelial wound healing. We will determine the effect of Fyn, an SFK member, in in vivo corneal epithelial wound healing using genetically-modified mice; and in in vitro human organotypic corneal wound model using lentiviral knockdown and overexpression of Fyn.
AIM 2) Define the effect of Srcasm on corneal epithelial wound healing. We will define the effect of Sracsm in in vivo corneal epithelial wound healing using genetically-modified mice; and in in vitro human organotypic corneal wound model using lentiviral knockdown of Srcasm.
AIM 3) Determine the molecular and transcriptional profile of ocular surface squamous neoplasias (OSSN, which are the epithelial tumors of the ocular surface), as well as the effect of SFKs and Srcasm in the development of OSSNs. We will profile conjunctival OSSNs with immunohistochemistry and RNA sequencing; and characterize the effect of lentiviral-mediated Fyn overexpression and Srcasm knockdown in an in vitro conjunctival tumor model.
Blindness and visual impairment from ocular surface disorders affect over 23 million people globally, making it the second most common cause of blindness worldwide. Preventable cases of vision loss often result from wounds that heal with opacification of the ocular surface. Understanding the pathways that regulate wound healing is critical to identifying therapeutic targets that may be helpful in promoting wound healing that preserves vision. Given biological similarities between wound healing and neoplasia, examination of these pathways will also provide new insights into the growth of ocular tumors. Therefore, a study that investigates both wound healing with tumorigenesis will provide comprehensive knowledge of molecular pathways that will lead to new potential therapies.
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