Improving Cardiac Function After Myocardial Infarction

Summary

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

Top Publications

  1. pmc Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling
    Hui 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
  2. pmc G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism
    Meryl 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
  3. pmc c-kit+ cells minimally contribute cardiomyocytes to the heart
    Jop 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
  4. ncbi Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy
    Maria Cecilia Scimia
    Temple University School of Medicine, Philadelphia, PA, USA
    Expert Rev Cardiovasc Ther 12:733-41. 2014
  5. pmc 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 arrhythmias
    Steven R Houser
    From the Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA
    Circ Res 114:1320-7; discussion 1327. 2014
  6. pmc Sorafenib cardiotoxicity increases mortality after myocardial infarction
    Jason 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
  7. pmc Cardiovascular gene therapy for myocardial infarction
    Maria C Scimia
    Temple University, Translational Medicine Pharmacology, 3500 N Broad Street, Philadelphia, 19140, USA
    Expert Opin Biol Ther 14:183-95. 2014
  8. pmc Myofibroblasts: trust your heart and let fate decide
    Jennifer 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
  9. pmc Cardiac progenitor cells engineered with βARKct have enhanced β-adrenergic tolerance
    Mohsin Khan
    San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, California, USA
    Mol Ther 22:178-85. 2014
  10. pmc Adrenergic nervous system in heart failure: pathophysiology and therapy
    Anastasios Lymperopoulos
    Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, FL 33328 2018, USA
    Circ Res 113:739-53. 2013

Research Grants

  1. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
  2. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
  3. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  4. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
  5. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  6. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
  7. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
  8. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
  9. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  10. H. pylori-induced inflammation and gastric cancer
    Richard M Peek; Fiscal Year: 2013

Detail Information

Publications17

  1. pmc Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling
    Hui 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...
  2. pmc G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism
    Meryl 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
    ....
  3. pmc c-kit+ cells minimally contribute cardiomyocytes to the heart
    Jop 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. ..
  4. ncbi Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy
    Maria 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. ..
  5. pmc 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 arrhythmias
    Steven R Houser
    From the Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA
    Circ Res 114:1320-7; discussion 1327. 2014
    ....
  6. pmc Sorafenib cardiotoxicity increases mortality after myocardial infarction
    Jason 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...
  7. pmc Cardiovascular gene therapy for myocardial infarction
    Maria C Scimia
    Temple University, Translational Medicine Pharmacology, 3500 N Broad Street, Philadelphia, 19140, USA
    Expert Opin Biol Ther 14:183-95. 2014
    ....
  8. pmc Myofibroblasts: trust your heart and let fate decide
    Jennifer 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 ". ..
  9. pmc Cardiac progenitor cells engineered with βARKct have enhanced β-adrenergic tolerance
    Mohsin 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. ..
  10. pmc Adrenergic nervous system in heart failure: pathophysiology and therapy
    Anastasios Lymperopoulos
    Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, FL 33328 2018, USA
    Circ Res 113:739-53. 2013
    ....
  11. pmc 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 therapy
    Alessandro 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
    ....
  12. pmc Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms
    Jason 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...
  13. pmc Parsing good versus bad signaling pathways in the heart: role of calcineurin-nuclear factor of activated T-cells
    Jeffery 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...
  14. pmc T-type Ca²⁺ channels regulate the exit of cardiac myocytes from the cell cycle after birth
    Fang 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...
  15. pmc 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 targeting
    Mai 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...
  16. pmc Lost in transgenesis: a user's guide for genetically manipulating the mouse in cardiac research
    Jennifer 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...
  17. ncbi Imatinib activates pathological hypertrophy by altering myocyte calcium regulation
    Larry 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...

Research Grants62

  1. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  2. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  3. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  4. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
    ..The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2 ..
  5. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  6. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  7. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  8. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  9. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  10. H. pylori-induced inflammation and gastric cancer
    Richard M Peek; Fiscal Year: 2013
    ..abstract_text> ..
  11. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
    ..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
  12. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  13. Cellular Immunity to Category A-C Viruses in Humans
    ROBERT WILLIAM FINBERG; Fiscal Year: 2013
    ....
  14. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  15. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  16. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  17. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  18. Carbon monoxide mediated inhibition of intimal hyperplasia
    Edith Tzeng; Fiscal Year: 2013
    ....