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Chair(s): Zimbrick, John; Brenner, David
(MS047) Tales from the crypt: hierarchical modeling of genomic defense mechanisms related to radiation-induced cancers.
Hattis, Dale1, Russ, Abel1, Ericson, Jennifer1, Cox, Catherine1, Langlois, Ann1, Parakh, Seema1, Seth, Divya1, Goble, Robert*,1, 1 George Perkins Marsh Institute, Worcester, MA, USA
ABSTRACT- We present preliminary findings from an attempt to describe and model the system of feedback controls that governs the activity and effectiveness of the processes involved in the defense of genomic integrity against various forms of ionizing radiation. Significant observations for different levels of biological organization span a wide range of temporal scales from minutes to hours for processes within cells, to hours to days for cell replication, to the years of latency for the development of tumors. We have built a hierarchical dynamic modeling scheme that represents these three levels of organization and have illustrated its application to data for the crypts that produce the epithelial cells of the large and small intestine. This system has the advantage for analysis that the stage of differentiation of the cells maps to their position in the crypt. Radiation exposure experiments indicate that P53 induction and apoptosis responses are strongest just in the cell positions where they may be most important as defenses against genomic damage. The responses may exhibit oscillatory behavior in space that can be interpreted in terms of time using the known migration rates of cells up the crypts. The dynamics of P53 mediated responses, including dose dependent damped oscillations that have been observed in other experiments, provide important information for modeling the system of feedback controls that is centered on the ATM/P53/mdm2 family of signaling responses to genetic damage. These responses are exquisitely sensitive to ionizing radiation. Full modeling of dose-time-response relationships including low dose rates requires modeling approaches that take into account both the rates of generation and the rates of loss of apoptotic cells during and after exposures. We use the scheme and its illustration to identify useful experimental research approaches which can shed light on dose-time-response relationships for radiation carcinogenesis at low dose rates.
Key words: multi-stage models, colonic crypts, carcinogenesis, genomic defences
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