MECHANISMS AND SIGNIFICANCE OF HYPOXIA INDUCED G1 ARREST

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DESCRIPTION (Applicant's Description): This proposal is designed to provide the principal investigator, Lawrence Gardner, with the necessary scientific experience to allow for a successful transition to an independent clinician scientist. Dr. Gardner has been involved in research since high school. He graduated from the Yale University School of Medicine, after an additional year dedicated to research. Following the completion of medical school, Dr. Gardner pursued a residency in internal medicine, and then specialty training in hematology/oncology, all at The Johns Hopkins Hospital. Over the past two years Dr. Gardner has devoted over 90 percent effort to basic research in the laboratory of Dr. Chi Dang, a professor of Medicine and Oncology. During this time he has studied molecular responses to hypoxia in normal cells, and has become proficient in many standard molecular and cellular biology techniques. Drs. Gardner and Dang have made several novel observations during these studies. They have delineated the mechanism responsible for hypoxia-induced G1 cell cycle arrest, a fundamental response in normal cells. They have also identified several neoplastic cell lines that do not undergo a G1 arrest in hypoxia. In July 2000, Dr. Gardner will become an instructor in the Department of Medicine at the Johns Hopkins Medical Institution. Clinical duties, including teaching, clinic twice a month, and a month of consult attending, will occupy 20 percent of his time. His remaining effort will be dedicated to obtaining the training necessary for a gradual transition to independent status. The training proposed includes didactics, attendance at national and specialty meetings, and specific feedback from a formal committee. The research plan detailed in this application builds on the observations and skills obtained by Dr. Gardner in Dr. Dang's lab over the past two years. The investigators have determined that the key regulator of hypoxia-induced G1 arrest in normal cells is the transcriptional induction of the cyclin- dependent kinase inhibitor p27. The research project will first study the molecular signals by which normal cells induce p27 in response to hypoxia. They will then determine why some neoplastic cells do not arrest in hypoxia. Finally, using neoplastic cells that do not arrest in hypoxia, as well as methods they have developed to abrogate hypoxia-induced G1 arrest, they will determine the contribution of this G1 arrest in hypoxia's effect on genomic instability and radioprotection.