Research Project 8: Arsenic and ABC Transporters

$411,164P42FY2007ESNIH

Dartmouth College, Hanover NH

Investigators

Linked publications & trials

Paper 39425535 Paper 39166865 Paper 38821458 Paper 38760865 Paper 38740209 Paper 38694196 Paper 38521049 Paper 38509226 Paper 38385740 Paper 38347123 Paper 38074282 Paper 38070554 Paper 37840773 Paper 37662412 Paper 37269393 Paper 37235264 Paper 37066389 Paper 37031836 Paper 36952094 Paper 36873246 Paper 36668670 Paper 36632065 Paper 36574487 Paper 36541020 Paper 36284198 Paper 36162478 Paper 35998698 Paper 35952739 Paper 35947921 Paper 35759030 Paper 35717483 Paper 35292690 Paper 35182530 Paper 35131829 Paper 35081493 Paper 34981270 Paper 34882045 Paper 34785205 Paper 34775665 Paper 34732816 Paper 34702988 Paper 34559918 Paper 34532651 Paper 34494118 Paper 34358915 Paper 34299734 Paper 34211112 Paper 34153129 Paper 34151044 Paper 34091160 Paper 34050180 Paper 33999403 Paper 33964505 Paper 33935287 Paper 33934293 Paper 33927050 Paper 33826413 Paper 33674630 Paper 33449088 Paper 33445102 Paper 33360198 Paper 33358725 Paper 33310435 Paper 33235293 Paper 33221612 Paper 33195875 Paper 33129000 Paper 33117768 Paper 33075355 Paper 33038235 Paper 32968156 Paper 32791343 Paper 32633494 Paper 32548921 Paper 32514536 Paper 32463466 Paper 32242893 Paper 32164038 Paper 32142916 Paper 32047945 Paper 32007686 Paper 31883061 Paper 31844832 Paper 31760590 Paper 31759648 Paper 31741542 Paper 31738529 Paper 31710845 Paper 31685535 Paper 31561054 Paper 31541377 Paper 31527512 Paper 31521894 Paper 31412494 Paper 31410744 Paper 31308155 Paper 31289418 Paper 31253828 Paper 31247490 Paper 31243636

Abstract

The long-term objective of our research is to elucidate how arsenic (As) affects xenobiotic bioavailability anc increases the incidence of atherosclerotic disease, diabetes mellitus as well as several types of drug resistanl cancers. In this application, studies will focus on elucidating the effects of environmentally relevant levels oi As on the expression and function of two ABC (ATP Binding Cassette) transporters: the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance protein 2 (MRP2). CFTR is a C channel that plays an important role in salt homeostasis. MRP2 transports xenobiotics, including chemotherapeutic drugs, toxins, and arsenicrglutathione conjugates out of cells and, thereby, plays a role in xenobiotic excretion in bile and urine, protects the brain from xenobiotic and toxic compounds and limits th< intestinal absorption of drugs. The proposed studies are designed to test the hypothesis that arsenic modulates hormonal regulation of ABC transporter gene expression and function. Specifically, the hypothesis is that As is an endocrine disrupter that blocks cortisol-glucorticoid receptor activation of CFTR gene expression and, thereby, interferes with salt homeostasis, and that As regulates xenobiotic excretion anc bioavailability by regulating MRP2 gene expression in kidney, intestine and the blood brain barrier. To test the hypothesis three specific aims are proposed. Specific Aim #1 will test the hypothesis that As perturbs NaC homeostasis by inhibiting CFTR gene expression and function. Specific Aim #2 will test the hypothesis tha As modulates MRP2 gene expression and function, and thereby affects xenobiotic excretion am bioavailability. Specific Aim #3 will test the hypothesis that As modulates the expression of novel genes tha regulate MRP2 and CFTR. To these ends a combination of biochemical, molecular, and live cell imaging approaches will be employed to study the effects of As on CFTR and MRP2 gene expression and function in kidney, intestine, operculum and blood brain barrier. The proposed studies will be highly interactive with Projects 2, 4 and 5, and will utilize all of the Cores. These studies will enhance our understanding of the cellular mechanisms whereby As regulates ATP transporter gene expression and function.

View original record on NIH RePORTER →