Physiological Genomics of the Zebrafish Heart

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The successful completion of the Human Genome Project has highlighted a major need for experimental approaches designed to relate genomic information to complex physiologic phenomena in the whole organism. The identification of those genes critical for the normal development of growth and function will be an important first step in the characterization of the underlying regulatory genomic networks. The zebrafish has proven an excellent model system for the study of the genetic basis of cardiovascular form. Phenotype based genetic screens have revealed a series of unitary components in cardiogenesis helping to dissect the logic of development. This proposal extends this approach to mutations that perturb early heart growth and/or function, in a broad way exploring the feasibility of a physiologic genomics effort. The project has two specific aims: 1) To clone positionally the mutated genes responsible for 40 physiologic phenotypes isolated from large genetic screens. These phenotypes are those in which the heart tube forms initially, generates chambers, but then fails to grow normally or to contract vigorously and with proper rhythmicity. 2) To systematically characterize the phenotypes and to begin to more precisely categorize the phenotypic effects in vivo and at the level of both organ and cell. All mutations will be made immediately available to the community, annotated by gene mutation and progressively refined phenotypic information. This unique resource will provide the entry points for subsequent investigation in zebrafish, other organisms and eventually humans, of those pathways central to the normal growth and function of the cardiovascular system.