Adult mammalian cardiomyocytes are terminally differentiated cells with very limited capabilities to divide, thus, injury to the heart typically causes permanent loss of muscle mass leading to ventricular dysfunction and heart failure. Therefore, a better understanding of how the myocyte cell cycle is controlled should enhance our ability to provide effective therapy for several heretofore-intractable cardiac diseases. Several studies indicate that the cardiomyocyte growth state in the developing heart correlates with regulated shifts in the expression of extracellular matrix and integrin receptors and the ability of these matrices to support myocyte growth in vitro. These data underscore the importance of integrin signaling in regulating both cardiac morphogenesis and the progression of cardiac disease, but how these processes are fine-tuned during the different phases of cardiac growth is unknown. It is clear from our studies completed within the past funding cycle that FAK functions to mediate cardiomyocyte proliferation during development, cardiomyocyte hypertrophy following pressure overload, and cardiomyocyte survival following an ischemic insult. We have also made the interesting discovery that FAK activity is dynamically regulated in the post-natal heart by expression of its endogenous inhibitor, FRNK. Our results demonstrate that FRNK is transiently expressed in the heart with peak levels occurring 5-7 days post-natal (just prior to cell cycle withdrawal) and that cardiac-selective expression of FRNK starting at E10.5 leads to a severe ventricular non-compaction defect and embryonic lethality associated with impaired cardiomyocyte proliferation and impaired coronary plexus formation. Importantly, ventricular cardiomyocyte-specific expression of a super-activatable FAK variant (bMHC-SuperFAK) was able to rescue this phenotype, indicating a cell autonomous role for FAK in regulating these critical functions. Thus, our working hypothesis is that dynamic regulation of FAK signaling is important for the control of cardiomyocyte cell cycle withdrawal during development and perhaps to cell-cycle re-entry in response to cardiac stress. We have generated many genetically modified gain-of-function/loss-of-function mouse models that will allow us to test this hypothesis and to identify the downstream signals that are important for the effects of FAK/FRNK on cardiomyocyte proliferation. In addition, since FAK signaling is regulated by, or required for, the effects of many of the environmental cues that regulate cardiac development and function, we strongly feel that the results from the proposed studies will have broad implications on our understanding of congenital cardiac disease and on the progression heart failure. We will utilize genetically modified mice, established cardiac cell culture models, and samples from a human heart repository to identify FAK-dependent mechanisms that regulate the pathogenesis of congenital and acquired heart disease.
We strive to understand the molecular mechanisms that regulate the ability of heart cells to divide, since strategies to manipulate this function could be efficacious in the context of several congenital heart diseases and heart failure. While heart cells can undergo division during development, alterations of the timing or locale of division can lead to congenital heart disease. Furthermore, these cells lose the ability to divide shortly after birth, thus any damage to the heart can cause irreversible loss of function.
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