Investigation of molecular mechanisms underlying the G2 and M cell cycle checkpoints in a cellular radiation response

Patients show variation in response to radiotherapy treatment, which can be detrimental to the patient. The precise cellular and molecular mechanisms responsible for this response are unknown, but it is known that radiation can result in genomic instabil ity within cells and this may be a key factor driving the molecular response. Assessing the ionising radiation response at a cellular level in vitro has proven to be a valuable tool in elucidating the molecular mechanisms which may be driving these varie d responses in patients. Our studies to date have shown that specific genes in the mitotic (M) checkpoint pathway of the cell are upregulated and downregulated with low doses of radiation in a cohort of individual colorectal carcinoma patient blood sampl es and colorectal cell lines. Furthermore, this molecular genetic response is attributable to cancer stage and gender of the test samples. Our studies highlighted the fact that in vitro cell cycle studies are important in elucidating an in vivo patient re sponse because of the clinical implications of the work conducted to date. Here, we propose to delve further into these molecular genetic studies of the cell cycle, to include the molecular genetics of the G2 checkpoint which operates prior to the M chec kpoint in the cell cycle. It is anticipated that this research will provide us with a more complete picture of the molecular mechanisms, which drive cell cycle events in a radiation response. It is anticipated that this novel research will generate 1-2 additional publications in international peer reviewed publications, and subsequently will be included into the applicant s final PhD thesis, due for completion in 2010. The research program will be carried out by the applicant at the Department of Radiat ion Biology in Radium Hospitalet in Norway with co-supervision from this laboratory and her own group at the Radiation and Environmental Centre in Dublin, Ireland. It is proposed that a synergistic collaborat