Over the past decade an explosive growth of knowledge has occurred regarding molecules that impact upon every aspect of myocardial biology via signal transduction cascades to activate or repress cellular processes. However, certain basic essentials of networking remain obscure despite widespread acceptance of signaling as a fundamental mechanism for myocardial regulation. For example, what controls the duration and intensity of a particular signaling pathway once activated? How do specific signaling cascade(s) achieve dominance among the cacophony of networked players and concurrent cross-talk or even competition between positive versus negative feedback? The answer, at least in part, can be found with a "molecular timer" that has yet to be studied in the myocardial context. This conductor of signal transduction, named Pin1, is a pivotal determinant of cellular proliferation, survival, commitment, and aging. Moreover, targets of Pin1 gleaned from published reports upon non-cardiac cells and tissues reveal a veritable "who's who" of cardioactive molecules that influence virtually every aspect of myocardial biology. By musical analogy, Pin1 does not choose the song, but instead sets the beat and the tone that determines which signaling will be potentiated. This proposal will delineate a novel mechanism for control of signaling duration and intensity in the myocardium. Accomplishing the stated aims of this proposal will reveal a previously unknown layer of regulatory complexity that integrates known myocardial signaling cascades, thereby offering new possibilities for coordinate control of molecular signaling to enhance resistance to pathologic damage and to potentiate regeneration and repair. The innovation of this proposal rests with the concept of coordination of signaling by Pin1 and reprogramming cellular responses in a multifaceted fashion by altering a single nodal regulator. The short term goal is to determine the mechanistic basis of Pin1 action in cardiomyocytes, stem cells, and the intact myocardium and assess the consequences of manipulating Pin1 activity to improve resistance to damage and enhance reparative processes.
Specific aims will demonstrate: 1) Myocardial survival, proliferative, and hypertrophic signaling are orchestrated by Pin1, 2) Loss of Pin1 activity leads to premature aging of the myocardium and associated decline in hemodynamic performance, and 3) Pin1 expression determines myocardial survival, resistance to pathological injury, hypertrophic remodeling, reparative potential, and antagonizes the molecular phenotype of aging. The significance of these studies is the widespread impact of Pin1 upon multiple canonical transduction cascades accepted as cornerstones of myocardial biology, meaning that the findings of this proposal will be relevant to a large proportion of the myocardial and regenerative medicine scientific community. Collectively, these studies will unlock a new facet of myocardial biology and challenge researchers to incorporate the influence of timing, intensity, and durability when delineating the fundamental basis of how the "music" of cellular signal transduction is ultimately chosen and played on the molecular level.
Heart disease remains a major cause of morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal focuses upon a novel fundamental molecular mechanism involving regulation of the timing and intensity for protective and regenerative signals in the heart to maintain cardiac structure and function resulting in extended quality of life and decreased medical cost.
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