Release of soluble factors is a well-known cellular stress response; however, we currently have little, if any, knowledge of how the type and amount of the factors released depends on the dose and quality of the radiation exposure. We are studying soluble factors released when cells are hit by electrons. These factors may induce responses in neighboring cells or "bystanders" that were not "hit". The soluble factors most likely to be involved in the cell-cell communication required for the bystander effect are small proteins secreted by cells and /or peptide fragments shed from the surface of a cell. A basic assumption of cancer risk analysis is that the probability of initiating cancer is proportional to the number of cells hit by radiation. In contrast, bystander effects potentially place all cells at risk in an irradiated tissue.

Project Goals:

Develop computer simulation techniques to model the induction of bystander effects. including the following processes:

1. Release of soluble factors by hit cells
   
   
2. Transport of these factors through the intercellular medium
   
   
3. Capture of soluble factors by cell-surface receptors
   
   
4. Intracellular signaling stimulated by ligand-receptor complexes

Research Approach:

Input data for these models will be generated in collaboration with the research being conducted at Pacific Northwest National Laboratory (PNNL). The PNNL microbeam facilities make it possible to control which cells are hit, the distance between "hit" cells and the number of electrons that hit each cell. Data about by transport, capture, and signaling by soluble factors from studies at PNNL will be used in our models to understand information processing by mammalian cells. In addition, results of experiments with engineered cell lines, which produce altered signaling proteins, provide information for the models on the extent that soluble factors can express their signaling influence. An understanding of the mechanisms involved in bystander effects is important for proper assessment of health risks from radiation exposure.

Expected Outcomes:

1. Information on what signaling factors are important in production of bystander effects
2. Understand the natural components of the development and function of multicellular organisms that are stimulated by radiation in an attempt to mount an appropriate tissue response
3. Determine how the total tissue response is related to radiation dose and risk.