This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. P-glycoprotein (P-gp), encoded by the ABCB1 gene, is an efflux drug transporter that is highly expressed in tissues important in drug disposition including the blood-brain-barrier (BBB). P-gp transport at the BBB protects the brain from potentially damaging substances circulating in the blood by effluxing xenobiotics from the endothelial cells that comprise the BBB. The role of P-gp in the transport of drugs is well known;however, less is understood about its importance in the transport of other xenobiotics, including environmental toxins. Recent reports have suggested that P-gp influences susceptibility to Parkinson's disease, perhaps by effluxing environmental neurotoxins from the brain and limiting their brain accumulation. Several neurotoxins are implicated in the development of Parkinson's disease;however, it is not known whether they are P-gp substrates or if P-gp influences their penetration into the brain. The ABCB1 gene is highly polymorphic and it has been shown that pharmacogenomics in ABCB1 influence drug efficacy and toxicity. We hypothesize that ABCB1 pharmacogenomics may also be relevant in the susceptibility to Parkinson's disease. Our goals in this proposal are to 1) measure P-gp transport of neurotoxins associated with Parkinson's disease (MPP+, paraquat, rotenone, and 6-hydroxydopamine) and determine whether they are P-gp substrates and 2) estimate the impact of ABCB1 genetic variation on the P-gp-mediated transport of these neurotoxins. To accomplish our goals, we will utilize a recombinant LLC-PK1 epithelial cell system expressing either wild-type ABCB1 or a genetic variant of ABCB1 (1199GA, 1236CT, 2677GT/A, and 3435CT) that we have developed previously [1,2]. Transepithelial permeability studies will be used to measure neurotoxin transport in ABCB1 recombinant cells, and quantitation of neurotoxins will be performed using chromatography methods in collaboration with Dr. Fernando Cardozo-Pelaez's laboratory in CEHS. Our unique in vitro system provides the tool to study how xenobiotics move across a physiologic cell barrier, such as the BBB;and therefore, allow us to make a prediction on the distribution and accumulation of neurotoxins in the brain. While data suggest that P-gp may be neuroprotective in Parkinson's disease, evidence is lacking to confirm that P-gp is important in the transport of neurotoxins at the BBB. Our proposal will provide the missing in vitro evidence to measure P-gp-mediated transport of the neurotoxins associated with Parkinson's disease and to study the influence of ABCB1 genetic variation. The results from this proposal will provide the necessary preliminary data to support competitive, full-scale grant application to the NIH and publication of peer-reviewed manuscripts. This research may be especially important for people highly exposed to neurotoxic pesticides and herbicides, such as farmers and agricultural workers, and may have application in the rural health setting.
| Peters, Bridget; Ballmann, Christopher; Quindry, Tiffany et al. (2018) Experimental Woodsmoke Exposure During Exercise and Blood Oxidative Stress. J Occup Environ Med 60:1073-1081 |
| Ward, Tony J; Semmens, Erin O; Weiler, Emily et al. (2017) Efficacy of interventions targeting household air pollution from residential wood stoves. J Expo Sci Environ Epidemiol 27:64-71 |
| Biswas, Rupa; Trout, Kevin L; Jessop, Forrest et al. (2017) Imipramine blocks acute silicosis in a mouse model. Part Fibre Toxicol 14:36 |
| Sanchez-Contreras, Monica; Cardozo-Pelaez, Fernando (2017) Age-related length variability of polymorphic CAG repeats. DNA Repair (Amst) 49:26-32 |
| Ferguson, Matthew D; Semmens, Erin O; Weiler, Emily et al. (2017) Lung function measures following simulated wildland firefighter exposures. J Occup Environ Hyg 14:739-748 |
| Park, Sunyoung; Nevin, Andrew B C; Cardozo-Pelaez, Fernando et al. (2016) Pb exposure prolongs the time period for postnatal transient uptake of 5-HT by murine LSO neurons. Neurotoxicology 57:258-269 |
| Jessop, Forrest; Hamilton, Raymond F; Rhoderick, Joseph F et al. (2016) Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure. Toxicol Appl Pharmacol 309:101-10 |
| Gábriel, Robert; Erdélyi, Ferenc; Szabó, Gábor et al. (2016) Ectopic transgene expression in the retina of four transgenic mouse lines. Brain Struct Funct 221:3729-41 |
| Wang, Xiaobo; Olson, Jenessa R; Rasoloson, Dominique et al. (2016) Dynein light chain DLC-1 promotes localization and function of the PUF protein FBF-2 in germline progenitor cells. Development 143:4643-4653 |
| Yi, Feng; DeCan, Evan; Stoll, Kurt et al. (2015) Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures. Epilepsia 56:297-309 |
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