Candidate: My career goals are to become a leader in the study of wound healing and the development of regenerative therapies for cutaneous wounds. To achieve this I will undergo intensive training in the basic sciences in cutaneous biology and notch signaling as well as ethics in the conduct of research. This will include formal coursework, one-on-one mentorship, presentations at lab meetings, department and University-wide seminars and national meetings. I will lead a nascent team of investigators in the study of cutaneous biology to develop a scientific foundation for understanding the mechanisms of cutaneous wound healing. I will submit an RO1 application no later than year 4 of the award period. Finally, I will seek leadership positions in national organizations in order to enhance collaborative efforts in this area as well as direct attention and resources towards developing therapies and solutions for this problem. All of these steps will facilitate my successful transitin to independence. Environment: The University of Wisconsin is one of the premier research institutions in the United States with over 800 biologists on campus. The Department of Surgery enjoys a reputation as one of the top in the country in terms of federal funding and career development of surgeon-scientists. The Department has mobilized its significant resources in making a commitment to Dr. King's career development including guarantees for start-up funds ($220,000) and 9 months of protected time per year. In addition, Dr. King will be mentored by two exceptional scientists and very successful mentors on this campus (Drs. Allen-Hoffmann and Chen) as well as other outstanding faculty. These components will provide him with an optimal research environment that will ensure that his transition to independence is successful. Research: My long-term goal is to develop an independent research career as a clinician scientist focused on the development of novel and effective therapeutic interventions for the treatment of cutaneous wounds. The objective of this application is to determine the molecular mechanism of the Notch family in human and murine cutaneous wound healing. Our central hypothesis is that skin specific Notch family members play a significant role in cutaneous wound healing by differential regulation of proliferation, keratinocyte differentiation and stratificatio within the epidermis. We have developed this hypothesis based upon our preliminary data and the published work of Kopan, Dotto, Radtke, Fuchs and others The rationale for the proposed research program is that it expected to yield new insights into the molecular mechanisms of cutaneous wound healing through which a clinically relevant therapeutic intervention could be developed for the treatment of cutaneous wounds, while at the same time, providing me the means of establishing independence as a clinician scientist. We are well prepared to pursue these studies because of the commitment of our institution to develop both novel strategies for wound healing and independent clinician scientists. I have created a mentoring team and collaborators with all of the skills needed to guide me in my pursuit to gain an independent research program. We will achieve our objectives through the pursuit of the following specific aims:
Specific Aim #1 : Investigate the role of the Notch family in cutaneous wound healing utilizing chimeric K14 specific Notch1, 2, or 3 knockout mice. Our working hypothesis is that wounds created in K14 specific Notch knockout mice have decreased rates of closure and decreased barrier function.
Specific Aim #2 : Characterize the role of the Notch family in cutaneous wound closure and establishment of barrier function in wound healing modeled in monolayer and organotypic culture. Our working hypothesis is that inhibition of the notch pathway will lead to delayed closure, and decreased barrier function in wounds and that re-activation of the notch pathway will increase the rate of closure and improve the barrier function of the "healed" organotypic skin.
Specific Aim #3 : Characterize the ability of notch activation to heal in vivo wounds utilizing chimeric K14 specific Notch1, 2, or 3 knockout mice. Our working hypothesis is that activating notch will increase the rate of closure and improve the barrier function of the wounded skin.
We anticipate that the research proposed will provide novel and critically important insights into the molecular mechanisms of human skin differentiation and organization and unveil opportunities for the design of novel wound healing therapeutics.