Structure And Function Of Abc Transporters To Understand Persistence Of Global Marine Pollutants

<p>Marine pollution is of concern for human health through our exposure to contaminated food from the sea. What remains poorly understood is why some chemicals are persistent, accumulating in marine organisms and then in humans, while others are not. Multidrug resistance (MDR) transporters, belonging to the ATP Binding Cassette (ABC) family, are major biological determinants of intracellular chemical accumulation. While ABC transporters have been implicated as determinants of pollutant persistence, and used as tools for predicting availability and efficacy of drugs, they have yet to be systematically applied to understanding why certain pollutants accumulate. In this project, a research team at the Scripps Institute of Oceanography will work to develop a structural and functional understanding of multidrug (MDR) ATP Binding Cassette (ABC) transporters and their interaction with global marine pollutants. They will clone, express and purify MDR ABC transporters from sea urchins and other aquatic organisms, and determine their molecular structures. They will also test, in vitro, whether global, persistent pollutants are substrates, inhibitors or not bound (i.e. not recognized) by the transporters. They will extend findings from the in vitro assays to the cellular and organismal level using pollutant accumulation, cytotoxicity and fluorescence competition assays with recombinant marine proteins and morpholino antisense oligonucleotide-mediated loss of function assays in sea urchins, a tractable marine model system. In vitro and in vivo results from marine transporters will be assessed in parallel assays with mammalian (mouse and human) transporters to determine which interaction patterns are conserved, potentially leading to transfer of pollutants from marine organisms to man. The team already has in-hand preliminary data that indicate striking functional conservation of the major subfamily types of xenobiotic eliminating transporters in sea urchins and man. Broader Impacts: Given the potential risk to human health from marine pollution, there is a need to refine our ability to predict accumulation and develop new tools to enable design of safer chemicals. This project is expected to make significant advances toward that goal. The research team will include several postdoctoral researchers and graduate students. JOINT FUNDING BY NSF AND NIEHS: The original proposal on which this project is based (R01 ES021985-01) was submitted to the National Institutes of Environmental Health Sciences (NIH/NIEHS) in response to Funding Opportunity Announcement RFA-ES-11-013 , 'Oceans, Great Lakes and Human Health (R01)', an opportunity jointly sponsored by NSF. This project is cooperatively funded through separate awards from NSF and NIEHS.</p>