This new investigator proposal describes a 5-year training program for the development of a surgeon-scientist career in Pediatric and Fetal Surgery. After completing an MD degree, this investigator trained for 9 years in adult and pediatric general surgery that led to board certification in both of these fields. This time period included a near 3-year research fellowship under the mentorship of Timothy Crombleholme at the Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center (CCHMC). The main focus of this new investigator's work was the fetal regenerative wound healing response. He is currently an assistant professor of Pediatric and Fetal Surgery at Cincinnati Children's Hospital Medical Center. His career goals are to use this K08 award to support his commitment to develop as a highly skilled scientist and in the long term to transition to a successful, independent, NIH-funded surgeon-scientist. CCHMC has a long history of promoting and supporting young scientist careers. The institution has guaranteed the applicant 75% protected time to commit to his research effort. In the Department of Surgery, he is one of 20 general surgeons and there is strong departmental priority for research and ample resources to achieve this goal. In addition to the time commitment, the institution has provided a generous start-up fund package for the applicant, which includes lab space, research funds, and ancillary support for 5 years. In addition, since starting his faculty appointment in September 2009, the candidate has been awarded a highly competitive Procter Scholar Award that provides significant additional salary support and a KL2 that provides research funds and a rigorous oversight committee to monitor his progress for the current academic year. The cornerstone of the career development plan is an exemplary scientific advisory committee. The four scientists are from diverse backgrounds but prior collaborations exist within the group. Each member is considered an international authority in their field and more importantly have a long track record of supporting young scientists and providing effective mentorship. In addition, the candidate, in close consultation with the committee has outlined an educational plan that includes additional coursework, weekly lab meetings, national conferences, and an organized research plan to complete his training. This proposal investigates the underlying mechanism of the fetal regenerative phenotype. The applicant previously examined the role of IL-10 in the fetal wound healing response and the recapitulation of the fetal state in postnatal tissues via an attenuation of the inflammatory response. His new focus is to examine the IL- 10 mediated regulation of the extracellular matrix (ECM) in the fetal regenerative phenotype. The applicant developed a novel hypothesis that proposes IL-10 can result in the formation of a regenerative pericellular matrix by dermal fibroblasts via a STAT3-dependent mechanism. This concept of an immuno-modulator regulating the ECM is highly innovative. In the testing of this hypothesis, three aims are outlined.
Aim 1 is to define the importance of IL-10 to the fetal fibroblast phenotype at the cellular level and then determine if IL-10 can recapitulate the fetal state in adult fibroblasts.
Aim 2 elucidates the STAT3-mediated intracellular signal transduction of IL-10 in fibroblasts.
Aim 3 is an in vivo validation of the hypothesis that effects of IL-10 in the regenerative phenotype are STAT3 and HAS1 mediated. Completion of these three aims ensures that there will be a clearer understanding of the underlying mechanisms of """"""""fetal scarless wound healing"""""""" and that therapeutic targets may be identified for any disease characterized by excessive fibroplasia. Finally, the several new techniques and concepts learned during the 5-year grant period will facilitate the applicant's scientific training, thus providing him with new tools and hypotheses on which to build his future scientific career. In summary, this research and training proposal aims to understand the molecular mechanisms in the fetal regenerative response relative to wound healing. The grant in conjunction with an expert, experienced mentorship panel and strong institutional support would provide a highly innovative, supportive platform for this young surgeon-scientist to finish his scientific training and make the transition to independent investigator in the field of regenerative medicine.
The proposed research and training is relevant to the public health because each year over 100 million patients acquire scars, some of which cause considerable morbidity. In contrast, mid-gestation fetal skin is known to heal a wound without scar. The underlying mechanism of this phenomenon is poorly understood. I test a novel hypothesis, that IL- 10 regulates fibroblast mediated regenerative extracellular matrix deposition via a STAT3-dependent mechanism representing a major mechanism in the fetal regenerative phenotype. The findings from the proposed research will provide significant insights into the underlying mechanisms of fetal scarless wound healing and may identify therapeutic targets for any disease characterized by excessive fibroplasia.
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