The overall goal of this grant proposal is to identify which elements of hemodynamic load are the primary mechanical determinants of cardiocyte mass and to define the intracellular signaling mechanisms which couple hemodynamic lead to the hypertrophic response. Three hypothesis will be tested: 1) normal cardiocyte structure and mass are the direct and ongoing result of a normal cellular loading environment and not a fixed property of the cardiocyte; this normal loading environment can be recreated in an in vitro cell culture model, 2) the active force developed and bourne by the cardiocyte during contraction (after-load), the passive resting sarcomere length (pre-load), and the cardiocyte contraction frequency (tension-time index) are the primary mechanical determinants of cardiocyte mass, and 3) these determinants differentially regulate cardiocyte mass through integrin-dependent cellular signalling pathways couple alterations in hemodynamic load to regulation of cardiocyte structure and mass. These hypothesis will be tested via three specific aims: 1) define the role that integrin-mediated cardiocyte adhesion plays in the ability to maintain adult mammalian cardiocytes in long-term primary culture using our newly developed in vitro model in which cardiocytes are embedded in a gel matrix environment which closely mimics the in vivo composite structure of the myocardium, 2) define the primary dynamic mechanical determinants of cardiocyte mass, and 3) define the mechanisms by which these primary mechanical determinants of cardiocyte mass are coupled to the cellular signaling pathways which transduce mechanical input into the cardiocyte hypertrophic response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048788-10
Application #
6631282
Study Section
Project Start
2002-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2002
Total Cost
$290,033
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Palanisamy, Arun P; Suryakumar, Geetha; Panneerselvam, Kavin et al. (2015) A Kinase-Independent Function of c-Src Mediates p130Cas Phosphorylation at the Serine-639 Site in Pressure Overloaded Myocardium. J Cell Biochem 116:2793-803
Baicu, Catalin F; Zhang, Yuhua; Van Laer, An O et al. (2012) Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload. Am J Physiol Heart Circ Physiol 303:H234-40
McDermott, Paul J; Baicu, Catalin F; Wahl, Shaun R et al. (2012) In vivo measurements of the contributions of protein synthesis and protein degradation in regulating cardiac pressure overload hypertrophy in the mouse. Mol Cell Biochem 367:205-13
Baicu, Catalin F; Li, Jiayu; Zhang, Yuhua et al. (2012) Time course of right ventricular pressure-overload induced myocardial fibrosis: relationship to changes in fibroblast postsynthetic procollagen processing. Am J Physiol Heart Circ Physiol 303:H1128-34
Mukherjee, Rupak; Snipes, Jonathan M; Saunders, Stuart M et al. (2012) Discordant activation of gene promoters for matrix metalloproteinases and tissue inhibitors of the metalloproteinases following myocardial infarction. J Surg Res 172:59-67
McCurdy, Sarah M; Dai, Qiuxia; Zhang, Jianhua et al. (2011) SPARC mediates early extracellular matrix remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 301:H497-505
Bradshaw, Amy D; Baicu, Catalin F; Rentz, Tyler J et al. (2010) Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298:H614-22
Mukherjee, Rupak; Zavadzkas, Juozas A; Rivers, William T et al. (2010) Short-term disruption in regional left ventricular electrical conduction patterns increases interstitial matrix metalloproteinase activity. Am J Physiol Heart Circ Physiol 299:H217-24
Chinnakkannu, Panneerselvam; Samanna, Venkatesababa; Cheng, Guangmao et al. (2010) Site-specific microtubule-associated protein 4 dephosphorylation causes microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem 285:21837-48
Mukherjee, Rupak; Rivers, William T; Ruddy, Jean Marie et al. (2010) Long-term localized high-frequency electric stimulation within the myocardial infarct: effects on matrix metalloproteinases and regional remodeling. Circulation 122:20-32

Showing the most recent 10 out of 136 publications