Citation:

PRESTON, J. RISK 0301 - MOLECULAR MODELING. Chapter M, John Wiley & Sons Incorporated, New York, NY, , 1101-1104, (2008).

Impact/Purpose:

Contribution to Risk Assessment Encyclopedia with emphasis on molecular modeling.

Description:

Risk assessment practices, in general, for a range of diseases now encourages the use of mechanistic data to enhance the ability to predict responses at low, environmental exposures. In particular, the pathway from normal biology to pathologic state can be dcscribed by a set of measurable key events. These key events can be considered molecular markers of disease. Recent advances in molecular biology methodologies and knowledge of the underlying mechanisms of several diseases have allowed for the identification of truly informative biomarkers of response, especially for tumors. The cancer risk from exposures to environmental chemicals can similarly be assessed using these types of molecular biomarker. Models of cancer have further enhanced the appreciation that tumor formation is a tissue response, and that modifications of normal biology need to be considered at a systems level rather than the gene or single pathway levels. Molecular models have been developed recently that are based upon such a systems approach: these include models of mitosis, cell signaling, nuclear transport and cell cycles. Abrogations of these systems can lead to disease outcomes. A very recent model based on gene-gene interactions among genes in C. elegatzs involved in signaling pathways that are also mutated in human diseases has identified a set of highly connected 'hub' genes that can essentially enhance the effects of mutations in a range of different genes. These 'hub' genes are all chromatin modulators, leading to a powerful approach for identifying key events in disease etiology. This type of molecular modeling, systems approach marks the way forward for incorporating key events into the risk assessment process for a range of diseases.

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