The Program Project Grant will integrate aspects of signal transduction that underlie normal and abnormal cardiovascular function and development. The Program is unified technically in using the approaches of gain- and loss-of-function in cell culture and in the mouse. Signaling pathways in normal cardiac development and function, the basic biology of cardiac signal transduction, and their intersections with the overall stress response will be studied. The Program consists of 4 Projects and 3 Cores. Project 1: Pathogenic signaling in cardiomyopathy will focus on understanding how mutations in a general chaperone, alpha-B crystallin (CryAB) can affect global cardiac function during stress response signaling. As each of the other Projects proposes to modulate specific signaling pathways, it is important to integrate the end response(s) with global cellular events in the cardiomyocyte. Project 2: The Akt-FoxO pathway in heart development will study the FoxO subfamily of the forkhead-related transcription factors. The members of this subfamily participate in regulating proliferation, differentiation and control of cell size in postnatal cardiac, skeletal and smooth muscle lineages. Project 3: The ERK-MAPK signaling branch in the heart will focus on the ERK pathway, one of the three branches of the MAPK signaling pathway. The hypothesis of the project is that ERK1/2 signaling is both necessary and sufficient in mediating physiologic and pathophysiologic cardiac hypertrophy. Although many investigators assume this is the case, with over 100 reports studying the pathway using cultured cells, a careful reading of the literature shows that almost nothing has been reported in vivo as to the necessary and sufficient functions of MEK1-ERK1/2 signaling within the adult heart. Project 4: G-protein receptor kinases in cardiac development and stress adaptation will explore the G-protein receptor kinases (GRKs), which phosphorylate ligand-occupied beta-AR, thus uncoupling them from G-protein effectors and targeting them for internalization. The Administrative Core (A) will serve as the organizational focus. The HistoPathology/Physiology Core (B) will provide an integrated central facility for the necessary histology and pathology, as well as for the physiological analyses. The Adenovirus-Cardiomyocyte Core (C) will prepare virus, rat neonatal cardiomyocytes and fetal and adult mouse cardiomyocytes for the Projects.
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