Targeting GRK2 (BARK1) in Heart Failure

Summary

Principal Investigator: Walter J Koch
Abstract: Targeting GRK2 ([unreadable]ARK1) in Heart Failure ABSTRACT Heart Failure (HF) continues to grow in the country and is a burden to the health care enterprise. HF often occurs after myocardial injury or stress such as ischemia or pressure-overload with cardiac hypertrophy occurring first, followed by ventricular remodeling and a loss of contractile function and [unreadable]-adrenergic receptor ([unreadable]AR) -mediated inotropic reserve. The G protein-coupled receptor (GPCR) kinase 2 (GRK2 or [unreadable]ARK1) plays a key role in the dysregulation of [unreadable]AR signaling in the hypertrophied and failing heart. Studies in transgenic mice using a peptide inhibitor of GRK2 (known as the [unreadable]ARKct) and also cardiac-specific GRK2 knockout (KO) mice suggest that GRK2 is a target to improve contractile function and [unreadable]AR-mediated inotropic reserve in HF. Of interest to this competitive renewal application, new data with [unreadable]ARKct expression in hearts and emerging data from GRK2 KO mice suggest that there are consequences of GRK2 inhibition or gene silencing that go beyond [unreadable]AR-mediated contractile function. For example, cardiac GRK2 KO mice have significantly limited myocyte hypertrophy in response to left ventricular (LV) pressure-overload, a phenotype also seen in [unreadable]ARKct mice with higher transgene expression. This occurs without the mice going into HF suggesting that GRK2 and its activity facilitate maladaptive cardiac hypertrophy. These data support the increasing evidence that a large and dynamic "GRK2 interactome" exists in cells and extends GRK2 activity and regulation to proteins outside of GPCRs. Molecules shown to interact with GRK2 such as tubulin and Akt suggest that this GRK may play roles in adaptive myocyte shape and size as well as cell survival. In addition, GRK2 can be found in/on mitochondria in cardiac myocytes through novel protein-protein interaction via the amino-terminus of GRK2. Moreover, interesting data from non-myocytes have shown that GRK2 negatively affects insulin signaling and glucose metabolism. Specifically, GRK2 has been shown to inhibit the translocation of the glucose transporter, GLUT4, to cell membranes with consequential insulin resistance. Thus, regulation of glucose uptake, which is critical as an energy substrate in the ischemic and failing heart, could be an important novel target of GRK2 action. In this competitive renewal application we are interested in elucidating critical [unreadable]AR-independent actions of GRK2 in the heart and knowing whether [unreadable]ARKct-mediated GRK2 inhibition or loss of GRK2 expression promotes novel beneficial pathways in the stressed and compromised cardiomyocyte. The Central Hypothesis of this proposal is that GRK2 plays a critical role in pathological cardiac hypertrophy, ventricular remodeling and HF via mechanisms beyond GPCR desensitization, and this is determined by novel interactions and localization within the cardiomyocyte. Testing of this hypothesis will also show that lowering GRK2 expression is a novel strategy to improve the function of the failing heart. Our associated Specific Aims are: [1] To determine whether novel, non-GPCR desensitizing functions of GRK2 play a facilitative role in the pathogenesis of maladaptive cardiac hypertrophy;[2] To investigate the in vivo role of GRK2 in dysfunctional myocardial glucose uptake of ischemic myocardium and to determine the cellular mechanisms in myocytes of how GRK2 regulates glucose metabolism and insulin signaling;[3] To determine whether viral- mediated gene transfer of an artificial micro-RNA that targets and silences GRK2 expression offers a novel therapeutic strategy for pathological hypertrophy and ischemic HF.
Funding Period: 1998-09-30 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function
    Hajime Funakoshi
    Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA
    Circulation 114:2240-50. 2006
  2. pmc Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction
    Philip W Raake
    Department of Internal Medicine III, Cardiology, University of Heidelberg, Germany
    Circulation 125:2108-18. 2012
  3. ncbi Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor
    Jean Pierre Louboutin
    Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Alcohol 46:441-54. 2012
  4. pmc Cardioprotection of controlled and cardiac-specific over-expression of A(2A)-adenosine receptor in the pressure overload
    Eman A Hamad
    Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e39919. 2012
  5. pmc Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility
    David M Thal
    Life Sciences Institute and the Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
    ACS Chem Biol 7:1830-9. 2012
  6. pmc Induced overexpression of Na(+)/Ca(2+) exchanger does not aggravate myocardial dysfunction induced by transverse aortic constriction
    Jufang Wang
    Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
    J Card Fail 19:60-70. 2013
  7. 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
  8. 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
  9. pmc GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility
    Norma C Salazar
    Department of Pharmaceutical Sciences, Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA
    Cell Commun Signal 11:64. 2013
  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

Detail Information

Publications32

  1. ncbi Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function
    Hajime Funakoshi
    Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA
    Circulation 114:2240-50. 2006
    ..To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter...
  2. pmc Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction
    Philip W Raake
    Department of Internal Medicine III, Cardiology, University of Heidelberg, Germany
    Circulation 125:2108-18. 2012
    ..G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study...
  3. ncbi Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor
    Jean Pierre Louboutin
    Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Alcohol 46:441-54. 2012
    ..Finally, ethanol consumption protected myocardium following experimental ischemia/reperfusion...
  4. pmc Cardioprotection of controlled and cardiac-specific over-expression of A(2A)-adenosine receptor in the pressure overload
    Eman A Hamad
    Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e39919. 2012
    ..These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A(2A)-R may provide a novel new target for pharmacologic therapy in patients with cardiovascular disease...
  5. pmc Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility
    David M Thal
    Life Sciences Institute and the Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
    ACS Chem Biol 7:1830-9. 2012
    ..Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors...
  6. pmc Induced overexpression of Na(+)/Ca(2+) exchanger does not aggravate myocardial dysfunction induced by transverse aortic constriction
    Jufang Wang
    Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
    J Card Fail 19:60-70. 2013
    ..Alterations in expression and activity of cardiac Na(+)/Ca(2+) exchanger (NCX1) have been implicated in the pathogenesis of heart failure...
  7. 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...
  8. 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
    ....
  9. pmc GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility
    Norma C Salazar
    Department of Pharmaceutical Sciences, Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA
    Cell Commun Signal 11:64. 2013
    ..We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF)...
  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 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. ..
  12. pmc Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury
    Z Maggie Huang
    1Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Sci Signal 6:ra95. 2013
    ..Our findings suggest new insights into the mechanism of action of classic drugs used to treat heart failure and new therapeutic approaches to ischemic heart disease. ..
  13. pmc Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms
    Ashley Bathgate-Siryk
    Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S University Dr, HPD Bldg Room 1338, Fort Lauderdale, FL 33328
    Hypertension 63:404-12. 2014
    ..Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF. ..
  14. 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
    ....
  15. 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. ..
  16. pmc Involvement of nuclear factor κB (NF-κB) signaling pathway in regulation of cardiac G protein-coupled receptor kinase 5 (GRK5) expression
    Kazi N Islam
    Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 287:12771-8. 2012
    ..Taken together, our study demonstrates that NF-κB plays a critical role in the regulation of GRK5 transcription in myocytes and that this may translate to the significant expression changes seen in heart disease...
  17. pmc Gi-biased β2AR signaling links GRK2 upregulation to heart failure
    Weizhong Zhu
    Institute of Molecular Medicine, Peking University, Beijing 100871, China Weizhong Zhu, MD, PhD, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19107, USA
    Circ Res 110:265-74. 2012
    ..Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood...
  18. ncbi Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat
    Scott M MacDonnell
    Cardiovascular Research Center, Temple University, Philadelphia, PA, USA
    Am J Physiol Heart Circ Physiol 293:H3122-9. 2007
    ..In conclusion, CsA normalized the blunted beta-AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent sarcoplasmic reticulum Ca(2+) regulation...
  19. pmc Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes
    Jeffrey S Martini
    George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Proc Natl Acad Sci U S A 105:12457-62. 2008
    ..Moreover, significant HDAC activity can be found with GRK5 in the heart. Our data show that GRK5 is a nuclear HDAC kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on GPCRs...
  20. pmc Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction
    Anastasios Lymperopoulos
    Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328, USA
    J Biol Chem 285:16378-86. 2010
    ..GRK2 inhibition in the adrenal gland might represent a novel sympatholytic strategy that can aid in blocking HF progression...
  21. pmc GRK2 as a novel gene therapy target in heart failure
    Giuseppe Rengo
    Center for Translational Medicine and George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
    J Mol Cell Cardiol 50:785-92. 2011
    ..This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy"...
  22. pmc Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms
    Henriette Brinks
    George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA
    Circ Res 107:1140-9. 2010
    ..GPCR signaling pathways are regulated by GPCR kinases (GRKs), and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function...
  23. pmc A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse
    Erhe Gao
    Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson University, 1025 Walnut St, Room 302, Philadelphia, PA 19107, USA
    Circ Res 107:1445-53. 2010
    ..We developed a novel and rapid surgical method to induce MI that does not require ventilation...
  24. pmc Cardiomyocyte lipids impair β-adrenergic receptor function via PKC activation
    Konstantinos Drosatos
    Dept of Medicine, Columbia University, 630 West 168th St, New York, NY 10032, USA
    Am J Physiol Endocrinol Metab 300:E489-99. 2011
    ..Thus, several lipids that are increased in the setting of lipotoxicity can produce abnormalities in β-AR responsiveness. This can be attributed to PKC activation and reduced β-AR levels...
  25. pmc Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels
    Anastasios Lymperopoulos
    Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, Florida 33328, USA
    J Am Coll Cardiol 57:356-65. 2011
    ..We investigated whether adrenal beta-arrestin 1 (βarr1)-mediated aldosterone production plays any role in post-myocardial infarction (MI) heart failure (HF) progression...
  26. pmc Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3
    Ellina Cheskis Feiner
    Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Card Fail 17:253-63. 2011
    ..Caveolin-1 and -2 are expressed ubiquitously, whereas caveolin-3 is found only in muscle. The role of caveolin-3 in heart muscle disease is controversial...
  27. pmc G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia
    Michele Ciccarelli
    George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA
    Circulation 123:1953-62. 2011
    ..In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile...
  28. pmc G protein-coupled receptor kinases in normal and failing myocardium
    Zheng Maggie Huang
    Center for Translational Medicine and George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
    Front Biosci (Landmark Ed) 16:3047-60. 2011
    ....
  29. pmc Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling
    Xue Li
    Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA
    Circulation 124:572-81. 2011
    ..To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor...
  30. pmc Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density
    Xue Li
    Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Am J Physiol Heart Circ Physiol 301:H1932-40. 2011
    ....
  31. 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
    ....

Research Grants62

  1. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Blood Stem Cell Transplantation as Immunotherapy
    Samuel Strober; Fiscal Year: 2013
    ..The results are also expected to reduce the risk of graft versus host disease in patients given hematopoietic cell transplants to treat leukemia and lymphoma. (End of Abstract) ..
  4. Insulin Resistance and Myocardial Autophagy
    EVAN DALE ABEL; Fiscal Year: 2013
    ....
  5. The role of interleukin-18 in myocardial hypertrophy and failure
    Bysani Chandrasekar; Fiscal Year: 2013
    ..The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in myocardial hypertrophy and its transition to failure. ..
  6. Deciphering the role of the RNA-binding protein, FXR1, in cardiac muscle assembly
    Carol C Gregorio; Fiscal Year: 2013
    ..Furthermore, the discovery of mRNA targets regulated by FXR1 during normal development and in diseased states may identify novel therapeutic approaches for heart disease. ..
  7. Phase II Clinical Trial to Evaluate the Benefits of Postconditioning in STEMI
    Jay H Traverse; Fiscal Year: 2013
    ..Our clinical trial will investigate if the modification of reperfusion using a technique called Postconditioning will reduce the size of a myocardial infarction and improve LV function as measured by cardiac MRI at 3 and 12months. ..
  8. Mechanisms of Adenylyl Cyclase Effects in the Heart
    H Kirk Hammond; Fiscal Year: 2013
    ..In patients with heart failure, drugs that improve heart function by increasing cAMP levels have failed to reduce mortality. Our studies will determine if this modified AC6 molecule will be a suitable heart failure treatment. ..
  9. A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling
    Qinghang Liu; Fiscal Year: 2013
    ..Furthermore, the proposed research will be of significance because what is learned here will also contribute to improved understanding of cell survival and homeostatic regulation in other cellular systems and disease models. ..
  10. Novel Methods for Cardiac Micro-Impedance Measurement
    ANDREW EMIL POLLARD; Fiscal Year: 2013
    ..Thesaurus Terms: electrical impedance, electrical measurement, heart electrical activity, interstitial, intracellular, method development, cardiac myocyte, electrical conductance, membrane model, myocardium, electrode. ..
  11. Controlled Chemotaxis and Differentiation of Embryonic Cardiac Progenitor Cells
    Gregory M Fomovsky; Fiscal Year: 2013
    ..The proposed research uses rigorous approaches to investigate these mechanisms in cardiac progenitor cells, and may lead to the design of successful cell therapies. ..
  12. SALsalate to Improve Exercise toleraNce and LVDD in T2dm-DHF (SALIENT-DHF trial)
    DOUGLAS LOWELL MANN; Fiscal Year: 2013
    ..3. Implement a HF-specific curriculum: a) weekly CV seminars;b) quarterly HF lecture series;c) yearly HF symposium;d) HF Visiting Professorship;and e) optional external rotations. ..
  13. Cardiac Myosin Binding Protein-C: Structure and Function
    Sakthivel Sadayappan; Fiscal Year: 2013
    ..abstract_text> ..
  14. Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship
    Steven Poelzing; Fiscal Year: 2013
    ..This model will include all the data collected from Drs. Poelzing, and Salama. The mathematical model will be validated against all interventions proposed in the animal experiments. ..
  15. Role of SIRT3 in alcoholic heart muscle disease
    Charles H Lang; Fiscal Year: 2013
    ..thereby providing a broad translational basis for our research focus and the potential for therapeutic development. ..
  16. Advancing Experimental Models to Study Intercellular Crosstalk of Cardiac Cells
    Ulrike Mende; Fiscal Year: 2013
    ..Furthermore, we anticipate that the models that will be developed and the insights gained in this project will facilitate research on intercellular crosstalk between other cell types in the cardiac field and beyond. ..
  17. Role of MicroRNA-499 in the Heart
    Joseph Shieh; Fiscal Year: 2013
    ..Shieh's career development. UCSF and Gladstone provide an outstanding environment for training independent physician scientists, promoting collaborative research and fostering individual scientific development. ..
  18. Molecular Mechanisms of Stem Cell Engraftment
    CLAUDIA OLIVEIRA RODRIGUES; Fiscal Year: 2013
    ..Insights developed from this grant could provide a significant translational advance in the new area of cell-based therapy. ..
  19. Novel Mechanisms and Therapies in Heart Failure
    Howard A Rockman; Fiscal Year: 2013
    ..The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure. ..
  20. Role of EHD proteins in cardiac excitability and disease
    Jerald W Curran; Fiscal Year: 2013
    ..The work completed here will be the firs to characterize the functional molecular mechanisms underpinning both protein trafficking and electrical remodeling within the heart. ..
  21. Period in Cardio Protection
    Tobias Eckle; Fiscal Year: 2013
    ..Targeting such pathways will lay the groundwork for novel and specific therapeutic approaches in the treatment of MI, which are urgently needed to improve morbidity and mortality. ..
  22. STIM1 mediated calcium entry: A new paradigm of metabolic regulation of cardiomyo
    John C Chatham; Fiscal Year: 2013
    ....
  23. Protective signaling mechanisms of the alpha1A-adrenoceptor
    Dianne M Perez; Fiscal Year: 2013
    ....
  24. The role of microRNA210 in cardiomyocyte response to ischemia-reperfusion
    Hossein Ardehali; Fiscal Year: 2013
    ..As of now, there are no medicines that can protect heart cells from dying. We propose to study the role of a newly identified biological process called microRNA to reduce damage to the heart from a heart attack. ..
  25. 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. ..
  26. Resynchronizing the Failing Heart: Insights from a Multiscale Cardiac Model
    Natalia A Trayanova; Fiscal Year: 2013
    ....
  27. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  28. Molecular Pathogenesis of Protein Surplus Cardiomyopathy
    Xuejun Wang; Fiscal Year: 2013
    ..abstract_text> ..
  29. Role of mitochondria in cardiac ischemia
    Peifeng Li; Fiscal Year: 2013
    ..abstract_text> ..