Project Grant R21AG077036

REGULATION OF MECHANICAL COUPLING IN AGING MYOCARDIUM - PROJECT SUMMARY AGE MODIFIES HEART STRUCTURE AND FUNCTION, EVEN IN THE ABSENCE OF OVERT CARDIOVASCULAR DISEASE. WITH AGE-RELATED CARDIAC REMODELING, THE HEART UNDERGOES EXTENSIVE CELLULAR AND MOLECULAR CHANGES THAT RESULT IN A STIFFER LESS COMPLIANT HEART THAT EXPERIENCES AN OVERALL DECLINE IN FUNCTION. YET, THE HUMAN HEART IS CAPABLE OF FUNCTIONING FOR DECADES DESPITE MINIMAL CELL TURNOVER OR REGENERATION, SUGGESTING THAT SOME MECHANISMS OF AGE-RELATED CARDIAC REMODELING MAY BE COMPENSATORY AND BENEFICIAL, HELPING SUSTAIN HEART FUNCTION OVER OUR LIFE SPAN. RECENT EVIDENCE INDICATES THE UPREGULATION OF CYTOSKELETAL PROTEINS MAY REPRESENT A CARDIOPROTECTIVE MECHANISM IN THE AGING HEART. IN THIS EXPLORATORY R21 PROPOSAL, WE HYPOTHESIZE THAT ENHANCING THE CYTOSKELETAL CONNECTION BETWEEN N-CADHERIN AND THE CORTICAL ACTIN NETWORK REPRESENTS AN ESSENTIAL COMPENSATORY MECHANISM TO MAINTAIN FORCE TRANSMISSION IN THE AGING MAMMALIAN HEART. TO TEST THIS HYPOTHESIS, THE REGULATION OF VINCULIN, A FORCE-SENSITIVE CYTOSKELETAL PROTEIN, WILL BE INVESTIGATED DURING CARDIAC AGING IN MICE. THE FOLLOWING INTERRELATED AIMS ARE PROPOSED: (1) TO TEST THE HYPOTHESIS THAT ABL KINASE IS REQUIRED TO MAINTAIN MECHANO- ELECTRICAL INTEGRITY IN THE AGING HEART. (2) TO TEST THE HYPOTHESIS THAT INHIBITION OF TYROSINE PHOSPHORYLATION OF VINCULIN WILL PERTURB N-CADHERIN-CYTOSKELETAL CONNECTION LEADING TO ACCELERATED CARDIAC AGING. THE PROPOSED STUDIES WILL ALLOW MECHANISTIC INSIGHT INTO HOW THE MAJOR PREDISPOSING FACTOR IN HEART DISEASE, AGE, AFFECTS THE REMODELING OF N- CADHERIN JUNCTIONS AND MECHANICAL COUPLING IN THE AGING HEART.