MYOFIBRIL AND MYOFIBER FORMATION IN THE DEVELOPING HEART

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DESCRIPTION: (Modified from applicant's abstract) Normal development of the heart requires an interaction between the extracellular matrix and individual cellular components. A complex variety of interactions result in the cellular phenotypes and patterns necessary for efficient cardiac function. Formation of distinct patterns of myocytes appears to be coordinately associated with myofibrillogenesis. This coordination involves an interaction between the ECM, specific transmembrane receptors and the cytoskeleton. While much is known considering the assembly of myofibrils, little is known concerning the role of the cytoskeleton in alignment of sarcomeres or the attachment of myofibrils to membranes and organelles. The proposed studies will: 1) examine the role of ECM receptors (integrins), cytoskeletal components and nuclear lamins in myofibrillogenesis in vitro; 2) use specific antibody, antisense oligonucleotide probes and growth factors to perturb the formation of myofibrils; 3) compare the patterns and alterations seen in vitro to myofibrillogenesis in the whole embryo culture model; and 4) determine if altered myofibrillogenesis causes altered myofiber pattern formation of myocytes in whole embryo culture. Mouse fetal heart cells will be used in a unique culture system that produces myocytes with a phenotype similar to that seen in vivo. Initial investigations will examine the expression of vinculin, alpha-actinin, and integrins during myofibrillogenesis. Microinjection of antisense oligonucleotides and/or antibodies will be used to block inter- actions with myofibrils at critical times in development. Similar probes will be used in whole embryo culture to determine whether abnormal myofibrillo- genesis will result in abnormal fiber patterns.Together, these data will provide an enhanced understanding of myofibrillar assembly and its relation- ship to cardiac organogenesis.