Development of Xenopus as a Model to Study Congenital Heart Disease

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DESCRIPTION (provided by applicant): The objective of this proposal is to substantially increase protected research time in order to boost productivity on a currently funded R01 (and its pending renewal) while positioning the candidate to successfully compete for a second major grant (i.e. a new R01 or a project on a programmatic grant). The candidate holds a joint faculty position between two state universities located ~120 miles apart. Travel, teaching and service obligations leave 45% time available for research. Support by a K02 award would release the candidate from most teaching and service assignments, generating 80-95% time over the next five years to be spent exclusively on research. The overall objectives of the candidate's funded R01 and pending renewal are to discover fundamental mechanisms of heart development, and to determine how they are affected by laterality genes during cardiac (dys)morphogenesis. To achieve this, the candidate has established an experimentally-induced heterotaxy model in embryos of the frog, Xenopus laevis. The heterotaxy embryos exhibit abnormal cardiac and visceral organ L-R asymmetries that are accompanied by complex, congenital heart defects (CHDs). Using an innovative cell labeling strategy to produce the first L-R cell lineage map of the vertebrate heart, the candidate discovered that L-R cell lineage composition is anomalous in heterotaxy hearts, and that the L-R lineage defects co-localize with structural CHDs. Based on these results and others, the K02 Aims are to identify in Xenopus the cardiac cell populations that, together with working cardiomyocytes derived from the primary heart fields, build the heart: secondary heart field, cardiac neural crest, and cardiac conduction system. These Aims will be accomplished by spending "minisabbaticals" in leading labs to adapt functional (laser-assisted tissue ablation, echocardiography, optical activation mapping) and additional embryological techniques (caged fluorescent dextrans, tissue grafting) for use in Xenopus. This will be complemented by coursework and participation in professional meetings. Data from the K02 Aims will be used to propose and test novel hypotheses on the role that L-R lineage composition in various cardiac cell populations play in cardiac (dys)morphogenesis. The significance of this work will be to elucidate conserved mechanisms of heart development, which in turn, will identify genes and inductive processes that may cause CHDs if affected by genetic or environmental perturbations. (End of Abstract)