Role of Integrins in Cardiac Myocyte Function

Project: Research project

Project Details


DESCRIPTION (provided by applicant): The extracellular matrix (ECM) is an
important determinant of cardiac mechanics. It plays a structural role by
maintaining the alignment of myocytes and vessels and preventing myocyte
slippage during contraction. ECM also plays an active functional role as a
force transducer. Integrins, the predominant receptors for the ECM, link the
extracellular matrix with the intracellular cytoskeleton and activate signal
transduction pathways in response to ECM adhesion. They are essential for
normal cardiac development, cardiomyocyte differentiation, and sarcomere
assembly. Integrins not only mediate cell adhesion, but also serve as
co-receptors for growth factor stimulated pathways and as mechanotransducers.
We hypothesize that integrins function as important signaling modulators in the
heart sensing and responding to mechanical and endocrine stimuli to maintain
cardiac hemostasis. It is specifically hypothesized that integrin signaling
pathways integrate with signaling pathways from G-protein coupled receptors
(GPCR) to coordinately regulate the hypertrophic response of cardiac myocytes.
The objective of this proposal is to define the role of integrin mediated
adhesion and signaling in the morphological and transcriptional changes that
define the hypertrophic response pathway of cardiac myocytes. The proposed
studies will utilize a well characterized cell culture model of neonatal rat
ventricular myocytes and adenoviral gene delivery. First, we will determine the
effect of the expression of gain or loss of function integrin variants on
myocyte cellular organization and hypertrophic marker gene expression. Second,
we will determine the role of FAK in the integrin mediated cellular changes
associated with cardiac myocyte hypertrophy. Third, we will determine the
mechanistic basis of the relationship that couples integrin signaling to
hypertrophic response in myocytes induced by GPCR agonists. Studies will seek
to identify the point of convergence between GPCR mediated signaling and
integrin signaling pathways and the critical effector molecules of integrin
signaling that cooperatively regulate adrenergic signaling pathways in cardiac
myocytes. Overall, these studies will provide insights into the molecular
pathways that underlie the compensatory hypertrophic growth response as well as
the transition to cardiac failure. A greater understanding of cardiac myocyte
signaling pathways may lead to new therapeutic approaches applicable to
pathologic alterations found in the human myocardium.
StatusNot started


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