The hypothesis upon which this Program Project Grant is based is that hemodynamic loading of the heart is the primary regulator of its structure and function. While the prediction of this hypothesis are equally applicable to cardiac physiology, the question which we have chosen as the subject of these studies is that of how increased load interacts directly with the heart to explain the causes and consequences of cardiac hypertrophy. In this context, the five individual projects form a closely interrelated set of studies. In Project #1, Dr. McDermott, who has used cardiocytes and tissue loaded in vitro, and myocardium loaded in vivo, to define translational control in hypertrophy, will extend this work to the question of whether the increased translationally active eIF-4E that he finds is causally linked to hypertrophy. In Project #2, Dr. Carabello will build on this studies showing less hypertrophy in mitral regurgitation than aortic stenosis, with ventricular remodeling in the former but not in the latter, by asking how failure to re-normalize wall stress induces this process. In Project #3, Dr. Menick will extend his discovery of elements requisite for cardiac expression of the Na-Ca exchanges gene, as well as a novel element important for cardiac expression and hypertrophic upregulation, to studies of transcriptional regulation of a gene encoding a protein critical to calcium homeostasis in hypertrophy. In Project #4, Dr. Cooper will extend his work showing augmented microtubules in hypertrophied myocardium and microtubule stabilization and upregulation of microtubule proteins, to an attempt to establish a cause-and-effect relationship between these changes in gene expression and contractile dysfunction, with an emphasis on the role of isoform-specific changes in tubulin expression. Also, in a new initiative, we will explore our recent discovery suggesting that hypertrophic microtubule alterations may have a role in the altered beta-adrenergic receptor function suggesting that hypertrophic microtubule alterations may have a role in the altered beta- adrenergic receptor function characteristic of cardiac hypertrophy. In the new Project #5, Dr. Zile will exploit his development of a unique, phenotypically stable isolated adult cardiocyte model to study the signalling pathways by which load is coupled to growth in the adult cardiocyte. Thus, the first and fifth projects are concerned with causes of load-induced cardiac hypertrophy in the adult, with the first focused on inducting of increased protein synthesis, and the fifth focused on signals for that induction. The other three projects are concerned with consequences of load-induced cardiac hypertrophy in the adult, being focused on mechanisms by which changes in structural and regulatory elements, whether intracellular or extracellular, alter contractile function and its regulation in cardiac hypertrophy.
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