Elucidating a novel function for slco1a2, an organic anion transporter, in left-right patterning and cardiac development

Yale University, New Haven CT

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Abstract

? DESCRIPTION (provided by applicant): Congenital Heart Disease (CHD) is the most common birth defect affecting approximately 1% of all live births in the US and is one of the leading causes of infant mortality. A severe form of CHD can result from Heterotaxy (Htx), a disorder of Left-Right (LR) patterning during embryonic development. A recent genetic analysis of heterotaxy patients identified a novel CHD candidate gene, slco1a2. Slco1a2 encodes the organic anion transporter Oatp1a2, which is important for the transport of various endogenous molecules as well as drugs across the apical membrane. However, it has no known role in LR patterning or embryonic development. Using different knockdown/knockout strategies in the high-throughput human disease model, Xenopus, loss of slco1a2 leads to LR patterning defects, recapitulating the patient's phenotype. The overall goal of this proposal is to investigat the molecular mechanism by which slco1a2 affects LR patterning and heart development in the Xenopus (frog) model system. The first aim will use loss of function experiments to determine the required role of slco1a2 during cardiac development and then, by testing molecular markers, investigate at which step in the LR patterning cascade the gene plays a role. The second aim will investigate the spatial-temporal expression of slco1a2 mRNA in the whole embryo and examine the protein's sub-cellular localization in those tissues/times. The third aim will determine if the protein's known transport function is important for its role in LR patterning and cardiac development by mutating critical amino acid residues that affect the protein's ability to transport specific substrates. Altogether, these experiments will improve our understanding of cardiac development and the role of slco1a2 in the pathogenesis of CHD. In the future, this will benefit genetic testing and counseling, as well as improve outcomes in CHD because treatments can be tailored to genotype rather than solely on CHD phenotype. In addition, this application details the applicant's training plan including research mentorship, advanced coursework, training in new techniques, and the development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career performing patient-driven research as an independent physician- scientist.