PHYSICAL TRAINING EFFECTS ON THE HEART
Biography Overview This continuation grant will attempt to define important mechanisms which are responsible for the development of distinct types of adaptive cardiac hypertrophy in vivo. The isolated perfused heart and the heterotopic cardiac isograft will be employed to evaluate acute and more chronic responses. These model systems are devoid of neural innervation and will allow an assessment of the independent role of mechanical load, the renin- angiotensin system, alpha1 and beta adrenergic stimulation on the initiation and maintenance of the hypertrophic phenotype. Changes in heart weight, protein synthesis rates, and contractile protein biochemistry will be correlated both with activation of specific receptor coupled second messenger systems and with changes in early and late response gene expression in order to test the hypothesis that adaptive hypertrophy involves both common and distinct signalling pathways. In addition, cis acting regulatory elements of cardiac genes which are responsive to these same input signals will be identified using the newly developed techniques of in vivo gene transfer. Specific aims are: first, to define signalling mechanisms that are necessary and/or sufficient for the development of characteristic hypertrophic or genetic adaptation in normal hearts; second, to identify gender related mechanisms which influence the adaptive behavior of the heart; and third, to determine whether a hypertrophied heart (secondary to both a pathologic or a physiologic load) responds differently than a normal heart to an acute superimposed load. Finally, we will map regulatory elements in cardiac genes which are responsible for their altered expression in vivo in models of adaptive hypertrophy.
An understanding of the cellular and molecular mechanisms which define the distinct cardiac hypertrophic responses to pathologic and physiologic loads may lead to novel preventative and therapeutic approaches to cardiac muscle disease.
Time
|