The K-22 transition award mechanism is particularly suited to this physician-scientist at this point in the academic career trajectory. Together with a team of 3 basic science collaborators/mentors and various consulting experts, the applicant has an unusually rich environment upon which to draw. The UCSD Cancer Center provided space, equipment, and technical support for the applicant. The protected time away from clinical responsibilities will allow for publication, additional data gathering and analysis, and achievement of the realistic goal of being in a favorably competitive position for an R01 application by the end of the second year of the program as outlined. The limited postgraduate coursework will provide a unique opportunity to develop and apply mechanistic insight into the labwork. The K-22 translational award will enable this physician-scientist to compete successfully for independent advancement in a career combining basic science with a limited practice in academic radiation oncology. The central hypothesis is that significant complementation exists between cell cycle regulatory and DNA repair functions at G1 thru S phase (G1/S). Cyclin E function plays an important role in G1/S-phase mediated cell cycle control and DNA damage repair following IR, as reflected in the kinetics of the G1/S transition and the enhanced IR sensitivity parameters derived in the applicant's laboratory. To the extent present, cell cycle dependent cyclin E induced radiosensitization is, at least in part, influenced by expression of the S-phase DNA repair regulatory pathways involving Chk1, Mre-11, and Nbs-1. The proposed human glial tumor and murine transgenic radiation sensitivity experiments will likely develop a mechanistic understanding of the complementation between mammalian cell cycle and DNA repair pathways following ionizing IR-induced DNA damage thru G1/S. Furthermore, the rationale behind the analyses may have direct translational potential with respect to clinically relevant models of tumor initiation and radioresponse. Given the combination of strong interest in cell cycle regulation at G1/S, DNA repair following irradiation, intriguing radiobiologic glial and transgenic models of cyclin induction, and solid foundation in neurooncology, the applicant is well prepared to tackle these problems within the framework of the institutional resources and collaborative venues available at UCSD. The long-range goals are to formulate a mechanistic understanding of radiation sensitivity through potentially complementary mechanisms involving cell cycle regulation and the repair of radiation-induced DNA damage at G1 thru S phase (G1/S). Ultimately, it is hoped that the translation of such knowledge will enhance care in the radiation oncology clinic.
| Pardo, Francisco S; Lien, Winston W; Fox, Howard S et al. (2004) Parathyroid hormone-related protein expression is correlated with clinical course in patients with glial tumors. Cancer 101:2622-8 |
