The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with acute injury or chronic stress. Discovery of cardiac progenitor cells (CPCs) has established the heart as a dynamic organ with CPCs emerging as an efficacious choice for cardiomyoplastic repair. Myocardial structure and function is significantly improved by regenerative interventional approaches, but functional restoration of myocardial repair will inevitably require deciphering the molecular signaling that impairs cellular replacement and healing. The overarching premises of this proposal is that myocardial reparative mechanisms become compromised by pathologic stimuli leading to a downward spiral of cardiac insufficiency linked to inadequate cellular replacement. Specifically, this proposal delineates the relationship between ?-adrenergic receptor (?-AR) signaling and CPC-mediated reparative processes. ?-AR signaling regulates cardiac contractility and adaptation to physiological and pathological stress, but the impact upon maintenance of CPC function in response to acute injury and chronic stress has never been studied. Preliminary results indicate differential expression of ?1- versus ?2-ARs in uncommitted versus early cardiogenic CPCs, and this shift in receptor profile exerts profoundly divergent effects upon survival and proliferation. Therefore, short-term goals are to understand the consequences of ?-AR signaling for CPC function in the myocardium and extend these findings to develop therapeutic interventional strategies to empower CPC-mediated regeneration through manipulation of adrenergic drive. Translational potential of these findings will be explored using clinically relevant pharmacologic agents as well as a lentiviral vector engineered to express ?ARK-ct to improve survival, proliferation engraftment and commitment of CPCs in failing hearts.
Specific aims are: 1) ?2-adrenergic system regulates cardiac progenitor cell function, 2) CPC survival is antagonized by ?1-adrenergic receptor acquired during cardiac commitment, 3) CPC mediated myocardial repair is restored by ?-blockade in failing hearts, and 4) Regenerative potential of human CPCs is augmented by ?ARK-ct overexpression. The significance of the study is to understand the underlying molecular signaling affecting endogenous myocardial repair capability. Innovation rests with the novel intersection of adrenergic drive and wound healing in the myocardium, examined with a cutting edge combination of cellular, molecular, and animal models to cover the spectrum of basic studies that include human CPCs derived from heart failure patients: the exact target population that would benefit most from the successful completion of the proposed studies. The long term goal is to redefine perceptions of ?-adrenergic drive as "pathologic" and reveal the potential of leveraging adrenergic drive to enhance myocardial regeneration while concurrently preserving mature myocardium.
Heart disease, especially heart failure is a major public health issue in the United States with a considerable burden for the health care system. Despite recent progress in understanding the pathophysiology, heart failure still carries a 5-year mortality that rivals most cancers. This proposal focuses upon understanding how the environment of the damaged heart can impact upon repair and regeneration on a cellular and molecular level. Defining these issues on a mechanistic level will lead to novel approaches to enhance treatment of heart disease and aging.
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