Role of Integrins in Cardiac Myocyte Function

Project: Research project

Description

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.
StatusFinished
Effective start/end date9/30/017/31/06

Funding

  • National Institutes of Health: $269,500.00
  • National Institutes of Health: $269,500.00
  • National Institutes of Health: $269,500.00
  • National Institutes of Health: $269,500.00

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Cardiac Myocytes
Integrins
Muscle Cells
Extracellular Matrix
G-Protein-Coupled Receptors
Sarcomeres
Critical Pathways
Growth Factor Receptors
Cardiomegaly
Hemostasis
Mechanics
Cytoskeleton
Transducers
Cell Adhesion
Adrenergic Agents
Signal Transduction
Myocardium
Heart Failure
Cell Culture Techniques
Gene Expression

ASJC

  • Medicine(all)