Project 4: Genetic Susceptibility

$68,338P01FY2010ESNIH

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Paper 36516690 Paper 32106530 Paper 31740287 Paper 31501452 Paper 30624099 Paper 30254255 Paper 29662130 Paper 29634611 Paper 29047308 Paper 28796633 Paper 27836847 Paper 27553992 Paper 27523287 Paper 27517732 Paper 27325068 Paper 27238723 Paper 27120335 Paper 27104547 Paper 26870919 Paper 26826490 Paper 26685281 Paper 26472102 Paper 26418669 Paper 26329526 Paper 25723336 Paper 25463528 Paper 24997910 Paper 24865645 Paper 24792414 Paper 24625153 Paper 24594649 Paper 24561003 Paper 24342266 Paper 24328542 Paper 24301353 Paper 23466277 Paper 23408194 Paper 23264748 Paper 23261756 Paper 23123252 Paper 22884923 Paper 22772953 Paper 22767010 Paper 22425525 Paper 21775902 Paper 21673326 Paper 21636082 Paper 21252392 Paper 21093416 Paper 20945243 Paper 20883709 Paper 20706997 Paper 20540155 Paper 20493249 Paper 20350560 Paper 20338154 Paper 20221870 Paper 20221869 Paper 20221868 Paper 20061341 Paper 20025959 Paper 19890166 Paper 19620892 Paper 19560483 Paper 19371602 Paper 19322108 Paper 19146843 Paper 19136611 Paper 19103322 Paper 19071155 Paper 18974090 Paper 18957992 Paper 18929588 Paper 18711144 Paper 18631305 Paper 18543104 Paper 18470300 Paper 18463101 Paper 18033725 Paper 17955350 Paper 17936934 Paper 17204816 Paper 17084875 Paper 16835050 Paper 16835048 Paper 16773123 Paper 16601082 Paper 16495777 Paper 16353344 Paper 16337171 Paper 16263526 Paper 16251481 Paper 16249796 Paper 16203263 Paper 16203262 Paper 16203258 Paper 16112327 Paper 16102884 Paper 16007003 Paper 15977192

Abstract

The proposed studies aim to develop high throughput protocols for assessing OP exposures by characterizing specific biomarker proteins in blood, and to make use of these more accurate measures of exposure to investigate gene/environment interactions related to genetic variability in the paraoxonase (PONI) gene, particularly with respect to OP exposures that occur during early development. Specific Aim 1 is to validate high throughput immunomagnetic bead (1MB) based isolation protocols for rapid purification and analysis of the active site peptides of two proteins, red cell acyl peptide hydrolase (APH) and plasma butyrylcholinesterase (BChE), as biomarkers of exposure to OP compounds. A targeted proteomics strategy based on microcapillary liquid chromatography-selected reaction monitoring-mass spectrometry ([unreadable]mu[unreadable]LC-SRM-MS) will be validated and used to quantify the percentage modification of BChE and APH in archived samples from the Community Based Participatory Research Project. Data from the biomarker experiments will be correlated with other data available on urinary metabolite levels, inhibition of APH and/or BChE, and PONI status. Specific Aims 2 and 3 use knockout and humanized mouse models to determine the importance of PONI status for OP exposures that occur during critical periods of early development. Specific Aim 2 is to determine the extent to which APH and BChE are covalently modified following test exposure of pregnant mice to chlorpyrifos (CP) or CPO. Specific Aim 3 is to determine the extent to which BChE and APH are covalently modified following exposure of neonatal mice to CP or CPO. These aims will evaluate interactions among biomarkers of sensitivity, exposure and response in an in vivo system, allowing us to determine full dose responses of the OP compounds and generate quantitative biomarker data.

View original record on NIH RePORTER →