The investigator's hypothesis is that there are separable genetic pathways which configure the ventricle of the early embryonic heart. Their goal is to identify the genes essential to this patterning and to understand their cellular and embryological mechanisms of action. They focus upon four mutations we discovered which perturb formation of the ventricle in embryonic zebrafish: bs2lb, lonely atrium, and Pandora , mutants lack the ventricle, while the atrium is relatively preserved; heart and soul mutant embryos have ventricular tissue contained within the atrium of the early heart tube.
In Specific Aim 1, they propose to examine the hypothesis that these mutations perturb preventricular cells in the embryonic heart field, by examination of cell lineage and patterns of expression of myocardial genes in wild-type and mutant fish.
In Specific Aim 2, they propose to clone the four mutations by positional strategies. They believe that these genes provide important insights. First; they provide the necessary linchpins to begin molecular dissection of the steps which configure the ventricle. Second, they speak to an evolutionary issue, because the ventricle is a vertebrate-specific addition along the chordate lineage. Third, these genes may have relevance to congenital disorders, such as hypoplastic heart syndromes, and to potential therapeutic replenishment of contractile myocardium of the failing heart.
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