In the area of environmental carcinogenesis, Dr. States’ laboratory (Pharmacology and Toxicology) is focusing on the carcinogenic actions of arsenic, a natural contaminant of drinking water in many parts of the world.  Diseases often associated with chronic arsenic exposures include squamous and basal cell carcinomas of the skin, and these disorders have been linked to disruption of mitosis and apoptosis. 

Dr. States and his collaborators are interested in investigating the role of p53 in relieving the anaphase block induced by activation of the G2 checkpoint response by arsenite.  In their studies, a genomic approach is being utilized to discover novel molecular targets in the mammalian arsenite response and the critical gene-gene interactions that mediate the carcinogenic response to arsenic.  

Collaborative activities in the Center between the Ramos (Biochemistry) and Rempala (Mathematics) research groups have resulted in the development of a mathematical model to elucidate the molecular basis of LINE-1 (Long Intersperced Nuclear Element-1) retrotransposition.  Retrotransposons are mobile elements that propagate throughout the genome via an epigenetic mechanism that involves reverse transcriptase and RNA intermediates.  Retroelements influence gene expression and genome stability and have been implicated in the regulation of embryonic development and cellular differentiation (Stribinskis and Ramos, 2006).  A stochastic model of gene transcription based on coupled chemical reactions and a corresponding set of stochastic equations has been developed (Rempala et al., 2006) and will be expanded to explain reverse transcription and genomic integration of LINE-1 into mammalian genomes. 

These efforts will be facilitated by the availability of a bioinformatics and computational biology infrastructure that can catalyze continued interactions.  In separate studies, osteopontin, a matrix-associated protein and cytokine involved in regulation of differentiation and metastasis, has been identified as a gene that shares common regulatory networks with the aryl hydrocarbon receptor (Ahr), a PAS-homology domain transcription factor that mediates the biological effects of environmental polycyclic aromatic hydrocarbons (Johnson et al., 2004).  Further elucidation of these genes as “master” regulators of the biological response to environmental stress will also require a suitable infrastructure for promotion of collaborative activities.

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