This Component's long term objectives are twofold; 1) to understand normal and abnormal cardiac function in terms of the various contractile protein isoforms that are expressed; and 2) to explore the early developmental events that underlie normal and abnormal cardiogenesis. Towards the first goals, we will use transgenics to overexpress normal and mutated myosin light chains i the heart in a compartment specific manner such that athe protein complement of the heart is changed. Using cloned light chains and our cardiac specific promoters, a series of conditional transgenic animals will be made such that over expression and ectopic- isoform expression studies, as well as structure-activity studies can be done. Both the acute and chronic effects upon heart structure and function will be measured. These studies will use conditional expression transgenic models such that proteins encoded by the transgenes can be precisely modulated up/down during the animals' lifetime. The resultant mice will be analyzed at the molecular, biochemical, cellular and whole organ levels. In this manner, we will define whether or not a developing myopathy is due to a mutated protein and/or to stoichiometric perturbations in the levels of the contractile proteins that assemble to form the functional sarcomere. The second goal, to explore early cardiogenesis, involves the definition of the downstream targets of the morphogen, retinoic acid. We will use the a myosin heavy chain promoter to target a constitutively active retinoic acid receptor to the developing heart. The initial descriptive characterization will be followed by a concerted effort to identify the downstream genes that are activated, using a novel, dual screening approach. First, genomic fragments will be selected on the basis of t heir ability to bind the constitutively active retinoic acid receptor. These fragments will then be used to screen a normal genomic library. Clones isolated in this manner will then be screened with a probe population isolated via a differential PCR display obtained from developing hearts isolated from the mouse containing the constitutively active retinoic acid receptor and the nontransgenic littermates. In this manner, we hope to identify clones that are activated/deactivated by the morphogen's presence.
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