The general objective of this proposal is to define the role of tyrosine residue phosphorylation in the regulation of protein kinase C delta (PKCd) in myocardial tissue. The hypothesis to be tested is that agonist-specific activation of PKCd involves tyrosine phosphorylation which modifies PKC myofilament substrate specificity and kinase activity. Experiments will characterize tyrosine phosphorylation status on PKCd with various stimuli and the impact on myocyte mechanical function. In addition, the effect of tyrosine residue replacement with unphosphorylatable or pseudo-phosphorylated amino acids in the hinge, pseudosubstrate, and activation loop domains on PKCd localization and substrate specificity will be determined. Finally, experiments will resolve whether PKCd activation promotes the activity of other signal transduction pathways involved in regulation pathophysiological processes (hypertrophy or apoptosis. Compelling preliminary evidence indicates phosphorylation of specific tyrosine residues of PKCd alters substrate specificity particularly in respect to troponin (Tn) complex components. In addition, phosphorylated tyrosine (pY) may change the cofactor requirements of the kinase enabling lipid independent activity. Results will provide novel information regarding stimuli specific PKCd activation and activity as well as the effect on cardiac myofilament phosphorylation and myocyte functional capabilities. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL086023-01
Application #
7158009
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Meadows, Tawanna
Project Start
2006-08-16
Project End
2008-08-15
Budget Start
2006-08-16
Budget End
2007-08-15
Support Year
1
Fiscal Year
2006
Total Cost
$45,976
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612