Tales from the Crypt:
Hierarchical Modeling of Genomic Defense Mechanisms Related to Radiation-Induced Cancers

Why this Project?

To describe and model feedback controls that govern the activity and effectiveness of processes involved in the defense of genomic integrity against various forms of ionizing radiation. These defense processes include DNA repair of various types, systems of cell cycle checkpoint controls, and systems that trigger cell death by apoptosis in response to genomic damage, such as those mediated by P53.

Project Goals

To place observations of genomic feedback control processes in the context of the cell replication and differentiation pathways that occur in real tissues in humans and other mammals in order for them to be relevant for assessment of risks of cancer. The interpretations of these processes must be made at the sub-cellular level, the cellular level, and for systems of cells (tissues). They can then be extrapolated to humans and related human data.

Experimental Approach

1. Data will be compiled from a variety of cell system experiments describing such processes.
   
   
2. A hierarchical dynamic modeling scheme will be built that represents three levels of organization which span a wide range of temporal scales (processes within cells- minutes to hours, cell replication- hours to days and development of tumors- years).
   
   
3. The “crypts” that produce the epithelial cells of the large and small intestine will be used to illustrate the model’s application to data. This system has an advantage for analysis, in that the stage of differentiation of the cells maps to their position in the crypt. The “stem” cells that are the likely targets for carcinogenic transformation are located near the base of the crypt. As cell proliferation proceeds, daughter cells migrate up the crypt and differentiate—rendering themselves less vulnerable to carcinogenic transformation.

Expected Outcomes

1. P53 induction and apoptosis responses are the strongest in the cell positions where they may be most important as defenses against genomic damage.
   
   
2. 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.
   
   
3. 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.
   
   
4. Data drawn from only a single time point after the end of an exposure will not capture the full effects of the radiation over time, where exposure times are significant in relation to the development of the response.