Cardiac myocyte hypertrophy is an essential chronic adaptation, but it eventually becomes maladaptive resulting in the transition from hypertrophy to failure. Our long term objective is to identify mechanisms by which alterations in myofilament protein structure/function relations promote the hypertrophic response and the transition from compensated to decompensated hypertrophy. There is compelling evidence that modifications of the thin filament regulatory proteins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI), either by protein kinase C (PKC) phosphorylation or by switching to a mutant isoform, may be important in the transition between compensated hypertrophy and decompensation. Phosphorylation of cTnT and CTnI depress myofilament force generation and may be maladaptive. Our overall objective is to test the hypothesis that isoform switching of cTnT to mutant forms genetically linked to familial hypertrophic cardiomyopathy (FHC) alters functional effects of PKC dependent phosphorylation of both TnT and cTnI.
Our specific aims address the following questions:
Aim number 1. What is the relative significance of TnT PKC sites -Thr206, Thr 215, and Thr 295 - on Ca2+-dependent activation of myofilament force, crossbridge kinetics, and economy? Aim number 2. Are functional effects of cTnT or cTnI phosphorylation amplified or repressed in myofilaments containing cTnT-deltaexon 15,16 (missing 27 C- terminal amino acids including Thr 295)? Aim number 3. How is myofilament Ca2+-signaling involving protein-protein interactions of cTnT with CTnI and with cTnC altered by protein phosphorylation? These studies will provide important information relevant to our understanding of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010409-02
Application #
6402742
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Commarato, Michael
Project Start
2001-08-01
Project End
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$40,196
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Burkart, Eileen M; Sumandea, Marius P; Kobayashi, Tomoyoshi et al. (2003) Phosphorylation or glutamic acid substitution at protein kinase C sites on cardiac troponin I differentially depress myofilament tension and shortening velocity. J Biol Chem 278:11265-72
Burkart, Eileen M; Arteaga, Grace M; Sumandea, Marius P et al. (2003) Altered signaling surrounding the C-lobe of cardiac troponin C in myofilaments containing an alpha-tropomyosin mutation linked to familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 35:1285-93
Sumandea, Marius P; Pyle, W Glen; Kobayashi, Tomoyoshi et al. (2003) Identification of a functionally critical protein kinase C phosphorylation residue of cardiac troponin T. J Biol Chem 278:35135-44
Pyle, W Glen; Sumandea, Marius P; Solaro, R John et al. (2002) Troponin I serines 43/45 and regulation of cardiac myofilament function. Am J Physiol Heart Circ Physiol 283:H1215-24
Pyle, W Glen; Hart, Marilyn C; Cooper, John A et al. (2002) Actin capping protein: an essential element in protein kinase signaling to the myofilaments. Circ Res 90:1299-306
Communal, Catherine; Sumandea, Marius; de Tombe, Pieter et al. (2002) Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci U S A 99:6252-6