The challenge remains to identify the pieces of the intrinsic genetic and cellular puzzles that underlie acquired heart disease. 
PPG Schema: This diagram of a cardiac cell depicts the focus of each Project Leader and the interactions that are built into the PPG plan.
The spatio-temporal organization of Ca2+ signaling proteins as well as discretely localized signaling modules; (i.e. assembled multiprotein complexes) are crucial for defining signaling specificity within a cardiac myocyte. Proper heart cell function depends upon the intimate association between Ca2+ signaling elements in transverse-tubules as well as conduction macromolecules at gap junctions. These critical cardiac proteins are locally organized and regulated, in part, by the macromolecular architecture of scaffolding structural proteins as well as through segregated cellular signaling pathways (see PPG Schema above). The importance of the cytoskeleton proteins for proper cardiac function has been recently emphasized by its links to acquired and inherited dilated cardiomyopathies in animal models and human cardiac disease. In Project 1, Dr. Rogers examines the role of local control of protein phosphorylation by phosphatases, the role of phosphatases in control of cytoskeletal architecture at t-tubules and L-type Ca2+ channel function. The importance of phosphatase targeting will be further examined through ectopic expression of targeting motifs with adenoviral constructs and tested in animal models of heart failure. In Project 2, Dr. Bloch, through the use of transgenic mouse heart failure models, is examining the role of stress-activated signaling in disruption of cytoskeletal structures and loss of connexin-43 at gap junctions. A unique feature of this project is that a new inducible gene-switch transgenic model of cJun N-terminal kinase (JNK) is exploited to identify molecular mechanisms of stress-activated signaling on phosphatase retargeting, gap junction structures, and compromised Ca2+ signaling. In Project 3, Dr. Lederer is studying how Ca2+ signaling depends on filament proteins of t-tubule cytoarchitecture and on phosphorylation state of signaling proteins. A strength of this Program Project Team is that the experiments are organized into an integrated theme of in situ genetic physiology that includes a group of powerful interrelated approaches including viral gene transfer, biochemistry, cell biology, voltage clamp and high resolution Ca2+ imaging.
| Project 1:
Phosphatases, Local Structures, and Signaling in Heart Project 2:
Stress-activated Protein Kinases in the Regulation of Local Structure/
Function in the Cardiomyocyte Project 3:
Subcellular Organization
and Ca2+ Signaling in Heart Failure Funded by the National Heart, Lung, and Blood Institute.  |
