Improving Cardiac Function After Myocardial Infarction
Principal Investigator: Steven R Houser
Abstract: DESCRIPTION (provided by applicant): The goal of this program project grant is to develop novel approaches to prevent, slow or reverse the pathological structural and functional cardiac remodeling that takes place after a myocardial infarction (Ml). Ischemic heart disease is a major health problem with few effective therapies. Ml usually leads to congestive heart failure with premature death or severe functional disability. While many cardiac defects have been identified in the diseased heart, very few have been translated into novel therapies. The objective of this PPG is to define novel mechanisms of cardiac dysfunction after Ml and to test, in large animal models, novel approaches to block these pathological processes so that cardiac function is improved. The program involves 3 projects and 4 supportive cores. All project leaders are established investigators and they have all collaborated extensively over the past decade. Project 1 (Houser) will explore the idea that blocking excess Ca entry into microdomains that house pathological signaling molecules will reduce cardiac dysfunction and death after Ml. Project 2 (Molkentin) will determine if reducing the activity of PKC-alpha will promote increased myocyte contractility and reduce cell death. Project 3 (Koch) will interrupt abnormally activated adrenergic signaling cascades that lead to cell death and reduce new myocyte formation. Discovery experiments to define and validate those processes we hope to modify to improve post Ml structure and function will be done in small animal models. Final tests of developed therapeutic approaches will be done in a large animal model with structural and functional characteristics that are similar to those in humans, setting the stage for rapid translation of novel therapies to patients with ischemic heart disease. The 3 projects are supported by 4 cores. A large animal model (pig) core will perform all Ml procedures and cardiac evaluations. This core will also perform all therapeutic interventions. A cell and tissue core will perform small animal experiments and will evaluate the properties of cells and tissues from all animal studies. A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources.
Funding Period: 2012-05-07 - 2017-03-31
more information: NIH RePORT
- Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signalingHui Gao
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA
J Mol Cell Cardiol 53:657-67. 2012..While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs...
- G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolismMeryl C Woodall
From the Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, PA M C W, B P W, W J K and Department of Medicine and Surgery, University of Salerno, Salerno, Italy M C
Circ Res 114:1661-70. 2014....
- c-kit+ cells minimally contribute cardiomyocytes to the heartJop H van Berlo
1 Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA 2 Department of Medicine, Division of Cardiology, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA 3
Nature 509:337-41. 2014..008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level. ..
- Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapyMaria Cecilia Scimia
Temple University School of Medicine, Philadelphia, PA, USA
Expert Rev Cardiovasc Ther 12:733-41. 2014..Finally, hypothetical approaches to target APJ, taking into account its downstream pathways, will be described. ..
- Role of RyR2 phosphorylation in heart failure and arrhythmias: protein kinase A-mediated hyperphosphorylation of the ryanodine receptor at serine 2808 does not alter cardiac contractility or cause heart failure and arrhythmiasSteven R Houser
From the Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA
Circ Res 114:1320-7; discussion 1327. 2014....
- Sorafenib cardiotoxicity increases mortality after myocardial infarctionJason M Duran
From the Cardiovascular Research Center J M D, C A M, D T, P G, S H, J D, T E S, T S, R M B, H K, S R H, Center for Translational Medicine H L, R J V, D Y, E G, T F, and Department of Anatomy and Cell Biology M B, Temple University School of Medicine, Philadelphia, PA
Circ Res 114:1700-12. 2014..Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism...
- Cardiovascular gene therapy for myocardial infarctionMaria C Scimia
Temple University, Translational Medicine Pharmacology, 3500 N Broad Street, Philadelphia, 19140, USA
Expert Opin Biol Ther 14:183-95. 2014....
- Myofibroblasts: trust your heart and let fate decideJennifer Davis
Department of Pediatrics, University of Cincinnati, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
J Mol Cell Cardiol 70:9-18. 2014..This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ". ..
- Cardiac progenitor cells engineered with βARKct have enhanced β-adrenergic toleranceMohsin Khan
San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA
Mol Ther 22:178-85. 2014..Thus, βARKct engineering of CPCs promotes survival and proliferation of injected cells following myocardial infarction, which includes improved β-adrenergic tolerance essential for stem cell survival. ..
- Adrenergic nervous system in heart failure: pathophysiology and therapyAnastasios Lymperopoulos
Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, FL 33328 2018, USA
Circ Res 113:739-53. 2013....
- β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapyAlessandro Cannavo
Division of Geriatrics, Department of Translational Medical Sciences A C, G R, D L, G P, N F, D L, Department of Pediatrics and European Laboratory for the Investigation of Food Induced Diseases M V B, and Division of Cardiology, Department of Advanced Biomedical Sciences M C D A, R P, E D P, P C, B T, A R, Federico II University, Naples, Italy Center of Translational Medicine, Temple University, Philadelphia, PA A C, J E R, W J K Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme BN, Italy G R, C Z, N F and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom T M P
Circulation 128:1612-22. 2013....
- Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanismsJason M Duran
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
Circ Res 113:539-52. 2013..Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes...
- Parsing good versus bad signaling pathways in the heart: role of calcineurin-nuclear factor of activated T-cellsJeffery D Molkentin
Department of Pediatrics, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Howard Hughes Medical Institute, Cincinnati, OH 45229, USA
Circ Res 113:16-9. 2013..Since this time we and others have continued to uncover how this signaling effector pathway functions in the heart in regulating specific aspects of the growth response during disease and with exercise...
- T-type Ca²⁺ channels regulate the exit of cardiac myocytes from the cell cycle after birthFang Wang
Cardiovascular Research Center, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA
J Mol Cell Cardiol 62:122-30. 2013..The hypothesis examined in this study was the α1G TTCCs' influence in myocyte maturation and their rapid withdrawal from the cell cycle after birth...
- Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targetingMai Chen
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi an, China
Circ Res 112:1121-34. 2013..GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of β-adrenergic receptor kinase [bARKct]) is cardioprotective...
- Lost in transgenesis: a user's guide for genetically manipulating the mouse in cardiac researchJennifer Davis
Department of Pediatrics, University of Cincinnati, Howard Hughes Medical Institute, Cincinnati Children s Hospital Medical Center, 240 Albert Sabin Way, S4 409, Cincinnati, OH 45229, USA
Circ Res 111:761-77. 2012..This review uses examples from the field to illustrate the vast spectrum of experimental and design details that must be considered when using genetically modified mouse models to study cardiac biology...
- Imatinib activates pathological hypertrophy by altering myocyte calcium regulationLarry A Barr
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
Clin Transl Sci 7:360-7. 2014..There is evidence that imatinib can induce cardiotoxicity in cancer patients. Our hypothesis is that imatinib alters calcium regulatory mechanisms and can contribute to development of pathological cardiac hypertrophy...
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