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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL069779-10
Application #
8208020
Study Section
Special Emphasis Panel (ZHL1-PPG-D (O2))
Program Officer
Wong, Renee P
Project Start
2002-06-06
Project End
2013-08-31
Budget Start
2012-01-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$1,763,045
Indirect Cost
$543,785
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Molkentin, Jeffery D (2014) Letter by Molkentin regarding article, "The absence of evidence is not evidence of absence: the pitfalls of Cre Knock-Ins in the c-Kit Locus". Circ Res 115:e21-3
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Chakraborty, Santanu; Sengupta, Arunima; Yutzey, Katherine E (2013) Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts. J Mol Cell Cardiol 62:203-13
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Razzaque, Md Abdur; Gupta, Manish; Osinska, Hanna et al. (2013) An endogenously produced fragment of cardiac myosin-binding protein C is pathogenic and can lead to heart failure. Circ Res 113:553-61

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