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http://depts.washington.edu/sfund/projects/project_3.html
* PROJECTS
o Project 2: Mercury neurotoxicity in adults and children
o Project 3: Susceptibility to environmentally induced diseases
o Project 4: Environmental and genetic risk factors for Parkinson’s disease
o Project 5: Gene-environment interactions in coho salmon neurotoxicity
o Project 6: Remediation of organic pollutants using transgenic plants
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o Core A: Administration
o Core B: Research Translation and Outreach
o Core C: Functional Genomics and Bioinformatics Laboratory
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Project 3
Paraoxonases: biomarkers of susceptibility to environmentally-induced diseases
The overall aim of this project is to investigate various aspects of the functions and roles of two paraoxonases (PON1, PON2 and PON3) in determining susceptibility to environmentally-induced neurotoxicity and neurodegenerative diseases, with the goal of increasing confidence in their use as reliable markers of susceptibility for use in molecular epidemiology studies.
One aspect of the project focuses on the role of PON1 in modulating the toxicity and neurotoxicity of OPs derived from exposure to mixtures of these compounds. Carboxylesterases, which are crucial for detoxifying malathion/malaozon and pyrethroids, are inhibited by the oxons of chlorpyrifos and diazinon. Genetic variability of PON1 affects the detoxication of these oxons and thereby the sensitivity to malathion/malaoxon and pyrethroid exposures. A second aspect of the research examines the roles of PON1 and PON2 in Parkinson’s disease. More recent studies have examined the relationship of PON1 status to ALS. In related research, we have shown that low PON1 levels are a risk factor for carotid artery disease. The examination of other substrates of PONs 1, 2 and 3 have shown that all three of these proteins inactivate the quorum sensing factors of Pseudomonads.
Recent publications:
Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE. 2005. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenetics and Genomics 15:589-598.
Furlong C, Holland N, Richter R, Bradman A, Ho A, and B Eskenazi. 2006. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenetics and Genomics. 16:183-190.
Kelada SN, P Costa-Mallen, H Checkoway, CE Furlong, GP. Jarvik, HA Viernes, FM Farin, T Smith-Weller, GM. Franklin, WT Longstreth Jr., PD. Swanson, and LG Costa. 2003. Paraoxonase 1 promoter and coding region polymorphisms in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:546-547.
Jarvik GP, R Jampsa, RJ Richter, C Carlson, M Rieder, D Nickerson and CE Furlong. 2003. Novel Paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 13:291-295.
B. Eskenazi, K. Harley, A. Bradman, E. Weltzien, N. Jewell, D. Barr, C. Furlong, and N. Holland. 2004. Association of in utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Populations. Environ Health Perspect 112:1116-1124
Ozer EA, Pezzulo A, Shih DM, Chun C, Furlong C, Lusis AJ, Greenberg EP, Zabner J. 2005. Human and murine Paraoxonase 1 are host modulators of P. aeruginosa quorum-sensing. FEMS Microbiol Lett. 253(1):29-37.
Wills A-M, Landers JE, Richter RJ, Caraganis AJ, Cudkowicz ME, Furlong CE, Brown RH Jr. Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS. In press: Neurology.
© 2007 Department of Environmental and Occupational Health Sciences, University of Washington
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