Abstract
The research in pathogenesis of hypertrophy and heart failure has an important frontier in the study of cell signaling circuits involved in cardiomyocytes response to pathophysiological stimuli. The various circuits involved in this process have complex configurations, composed of proteins from distinct functional classes, including kinases, phosphatases, proteases, adapter proteins, chaperones and transcription factors.In previous studies we have explored proteins such as Shp2, FAK and ±B-Crystalline in cardiomyocytes response to mechanical and neurohumoral stimuli. The Shp2 tyrosine phosphatase is implicated in the regulation and development of adult myocardium, and mutations in this gene are associated with genetic syndromes such as Noonan and LEOPARD, heart disease and childhood cancer. Modulation of FAK by Shp2 is critical for hypertrophic signaling in cardiomyocytes, while the interaction of FAK with ±B-Crystallin FAK protects against degradation and promotes survival of cardiomyocytes. The ±B-Crystallin chaperone is a highly expressed in heart, acts in hypertrophic response modulation, integrity and activity regulation of signaling molecules.Although indirect evidences suggests the functional interaction between Shp2 and ±B-Crystallin in cardiac myocytes, both the nature and the functional importance of this interaction are still unknown. Thus, this project focuses on structural and functional studies of the interaction between Shp2 and ±B-Crystallin. Preliminary studies showed the interaction between ±B-Crystallin and Shp2 and this proposal comprises confirmation of these results, the determination of surface interaction, investigation of interaction influences in Shp2 activity and consequences in cardiomyocyte phenotype.The research in hypertrophy pathogenesis and heart failure have an important frontier in studies of cell signaling circuits involved in cardiomyocytes response to pathophysiological stimuli. The various circuits involved in this process have complex configurations, including proteins from distinct functional classes such as kinases, phosphatases, proteases, adapter proteins, chaperones and transcription factors.In previous studies we have explored the role of Shp2, FAK and alphaB-Crystalline proteins in cardiomyocytes response to mechanical and neurohumoral stimuli. The Shp2 tyrosine phosphatase is involved in heart development, and regulation of adult myocardium signaling, and mutations in this gene results in genetic syndromes such as Noonan and LEOPARD, heart disease and childhood cancer. Modulation of FAK activity by Shp2 is critical for hypertrophic signaling in cardiomyocytes, while the interaction of FAK with alphaB-Crystallin FAK protects against degradation and promotes cardiomyocytes survival. The alphaB-Crystallin chaperone is a highly expressed in heart, acts in modulation of hypertrophic response, integrity and in the regulation of signaling molecules.Although indirect evidences suggest the functional interaction between Shp2 and alphaB-Crystallin in cardiac myocytes, the nature and the functional importance of this interaction are still unknown. Thus, this project focuses on structural and functional studies of the interaction between Shp2 and alphaB-Crystallin. Preliminary results showed the interaction between alphaB-Crystallin and Shp2 in vitro and this proposal comprises confirmation of these results, determination of surface interaction, investigation of the role of this interaction in Shp2 activity and consequences in cardiomyocyte signaling and phenotype.The interaction between these proteins can elucidate a novel mechanism of protein activity regulation, in which alphaB-Crystallin can act as a platform for the stabilization of signaling molecules critical to cardiomyocytes. The details of the structure and function of complex signaling mechanisms may guide the emergence of new therapeutic approaches to diseases.
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