A 5-year research program is proposed to enhance an academic career in Pediatric Cardiology. The principal investigator has completed a residency in Pediatrics and a fellowship in Pediatric Cardiology. This career development plan will add depth to his scientific skills in the field of myocardial regeneration and heart failure. Two internationally renowned faculty members, David Clapham and Mark Keating, will sponsor the applicant. An advisory committee consisting of three leading scientists in their fields will provide the applicant with research and career advice. Humans do not regenerate their hearts. Instead, the human heart responds to injury with scar formation, not with proliferation, the cellular basis of regeneration. This inability to regenerate contributes significantly to cardiovascular morbidity and mortality. By contrast, lower vertebrates, e.g. newt and zebrafish, can regenerate their hearts by cardiomyocyte proliferation. Adult mammalian cardiomyocytes are believed to be quiescent, i.e. they do not proliferate. However, recent work in the Keating laboratory suggests that mammalian cardiomyocytes retain the latent potential to proliferate. The Principal Investigator focused on the identification of factors that release the proliferative potential of mammalian cardiomyocytes. Preliminary data indicate that periostin, a component of the extracellular matrix, stimulates cardiomyocyte proliferation. Periostin is absent from normal myocardium, but expressed in the injured heart. Our data support the hypothesis that periostin has a beneficial function in myocardial recovery.
The specific aims are: 1. Characterize the cellular effects of periostin in vitro: We will study the effect of periostin on cardiomyocyte cell cycle progression, proliferation, and survival in cultured primary rat cardiomyocytes. 2. Characterize the molecular function of periostin in vitro: We will characterize the receptor and the intracellular signaling pathways activated by periostin in cardiomyocytes. 3. Characterize the function of periostin in the heart in vivo: We will express periostin in the normal rat heart using adenoviral gene transfer. We will also pharmacologically disrupt the periostin action in rats with myocardial injury. We will evaluate the cardiac function with echocardiography and catheterization, and determine the tissue response with immunofluorescence microscopy. These studies will provide the first detailed functional analysis of periostin in the recovery of the injured mammalian myocardium. The long-term goal is to provide new therapeutic approaches to heart failure.
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