Phospholemman and Cardiac Contracility

Summary

Principal Investigator: Joseph Y Cheung
Abstract: DESCRIPTION (provided by applicant): Phospholemman (PLM), the 1st member of the FXYD family of small integral membrane proteins involved in regulation of ion transport, modulates the function of both Na+-K+-ATPase and Na+/Ca2+ exchanger (NCX1) in the heart. In the current grant period, using 3 model systems (adenovirus-mediated gene transfer in adult rat myocytes, transfected HEK293 cells, and PLM knockout (KO) mice), and different techniques (electrophysiology, biochemistry, radioactive tracer uptake, and site-directed mutagenesis), we have unequivocally established that PLM directly regulates NCX1 function, independent of its effects on Na+-K+- ATPase. We showed physical association between the cytoplasmic tails of PLM with the proximal intracellular loop of NCX1. Under conditions in which [Ca2+]o is raised to favor Ca2+ influx via NCX1, PLM regulates cardiac contractility mainly by modulating NCX1 rather than Na+-K+-ATPase activity. By contrast, when myocytes are Na+ loaded by rapid pacing and isoproterenol treatment, PLM limits inotropic response to b-adrenergic stimulation by enhancing Na+-K+-ATPase activity. Under baseline conditions, the effects of PLM on either Na+- K+-ATPase or NCX1 are not apparent. These results lead us to 2 hypotheses: (1) there is a small stretch of amino acid residues in the proximal linker domain of NCX1 that interacts with phosphorylated PLM;and (2) in the intact heart subjected to stress and therefore high catecholamine levels, PLM is phosphorylated at serine68 which simultaneously accelerates Na+-K+-ATPase but retard Na+/Ca2+ exchange activities. This coordinated action of PLM is necessary to minimize arrhythmogenesis and preserve inotropic response under b-adrenergic stimulation. In this competitive grant renewal, we wish to test our hypotheses by: (1) mapping out the exact sites/residues in NCX1 that are critically involved in its interaction with PLM;and (2) evaluate the mechanism by which PLM regulates cardiac contractility in hearts in vivo, both under resting and stressful conditions. We will use a combination of in vivo (echocardiography, catheterization, transduction of exogenous genes by rAAV9 injection) and in vitro (patch-clamp, single myocyte contractility and Ca2+ and Na+ measurements, co-immunoprecipitation and GST pulldown) techniques, focusing on 2 experimental model systems: transfected HEK293 cells and PLM-KO mice with inducible transgene (TG). We already have 2 genetically engineered mice (PLM-KO, inducible PLMS68E TG) on hand, and we are confident that given the resources, we will be able to generate inducible PLMS68E TG in PLM-KO background for our studies. We have found a NCX1 mutant (248-252 AAAAA) that exhibits normal NCX1 current but is not inhibited by PLM. By expressing this NCX1 mutant in NCX1-KO hearts (Dr. Kenneth Philipson has agreed to provide us the cardiac-specific NCX1-KO mouse), we should be able to critically test the physiological relevance of NCX1 regulation by PLM. We are the only laboratory that focuses on PLM and NCX1 interactions in the heart. We have all the reagents and techniques at hand and we believe we are well situated to critically examine the mechanism by which PLM regulates cardiac contractility. Alterations in phospholemman expression or its phosphorylation state are observed in ischemic cardiomyopathy and schizophrenia. In addition, the 2 classes of drugs (b-blockers and ACE inhibitors) that have been clinically found to be efficacious in congestive heart failure and ischemic heart disease may have PLM as a common target. Understanding how PLM regulates cardiac contractility in health and disease is therefore paramount for newer and rational therapy to be designed. PUBLIC HEALTH RELEVANCE: Phospholemman regulates 2 important ion transporters in the heart. This proposal uses 2 different genetically altered mice specifically engineered to critically evaluate whether regulation of sodium-calcium exchanger or sodium-potassium pump is the major mechanism by which phospholemman affects heart contraction. In addition, the exact molecular site in sodium-calcium exchanger interacting with phospholemman will be mapped out by mutagenesis.
Funding Period: 2003-12-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Phospholemman overexpression inhibits Na+-K+-ATPase in adult rat cardiac myocytes: relevance to decreased Na+ pump activity in postinfarction myocytes
    Xue Qian Zhang
    Department of Cellular and Molecular Physiology, Pennsylvania State University, Hershey, USA
    J Appl Physiol 100:212-20. 2006
  2. pmc Residues 248-252 and 300-304 of the cardiac Na+/Ca2+ exchanger are involved in its regulation by phospholemman
    Xue Qian Zhang
    Division of Nephrology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Am J Physiol Cell Physiol 301:C833-40. 2011
  3. 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
  4. pmc The transient receptor potential (TRP) channel TRPC3 TRP domain and AMP-activated protein kinase binding site are required for TRPC3 activation by erythropoietin
    Iwona Hirschler-Laszkiewicz
    Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 286:30636-46. 2011
  5. ncbi Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy
    Emanuele Giordano
    Department of Cellular and Molecular Physiology, The Penn State College of Medicine, Hershey, PA 17033 2390, USA
    Amino Acids 42:507-18. 2012
  6. pmc Cytosolic phospholipase A(2)α protects against ischemia/reperfusion injury in the heart
    Risto Kerkela
    Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Clin Transl Sci 4:236-42. 2011
  7. 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
  8. pmc Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity
    Tung O Chan
    Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Proc Natl Acad Sci U S A 108:E1120-7. 2011
  9. pmc Constitutive overexpression of phosphomimetic phospholemman S68E mutant results in arrhythmias, early mortality, and heart failure: potential involvement of Na+/Ca2+ exchanger
    Jianliang Song
    Division of Nephrology, Thomas Jefferson Univ, 833 Chestnut St, Suite 700, Philadelphia, PA 19107, USA
    Am J Physiol Heart Circ Physiol 302:H770-81. 2012
  10. pmc Phospholemman deficiency in postinfarct hearts: enhanced contractility but increased mortality
    M Ayoub Mirza
    Cardiovascular Division, Department of Medicine, University of Virginia Medical Center, Charlottesville, Virginia, USA
    Clin Transl Sci 5:235-42. 2012

Research Grants

  1. Quantitative analysis of cAMP compartmentation in heart
    Jeffrey J Saucerman; Fiscal Year: 2013
  2. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  3. Multi-scale Modeling of Calcium Mediated Triggered Activity in the Heart
    Yohannes Shiferaw; Fiscal Year: 2013
  4. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  5. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  6. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
  7. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  8. Regulatory Interactions of Cardiac Ion Pumps
    Seth L Robia; Fiscal Year: 2013
  9. GENE THERAPY FOR LONG-TERM MYOCARDIAL PROTECTION
    Victor J Dzau; Fiscal Year: 2013
  10. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013

Detail Information

Publications34

  1. pmc Phospholemman overexpression inhibits Na+-K+-ATPase in adult rat cardiac myocytes: relevance to decreased Na+ pump activity in postinfarction myocytes
    Xue Qian Zhang
    Department of Cellular and Molecular Physiology, Pennsylvania State University, Hershey, USA
    J Appl Physiol 100:212-20. 2006
    ..Inhibition of Na+-K+-ATPase by PLM overexpression, in addition to previously reported decrease in Na+-K+-ATPase expression, may explain altered V(max) but not K(m) of Na+-K+-ATPase in postinfarction rat myocytes...
  2. pmc Residues 248-252 and 300-304 of the cardiac Na+/Ca2+ exchanger are involved in its regulation by phospholemman
    Xue Qian Zhang
    Division of Nephrology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Am J Physiol Cell Physiol 301:C833-40. 2011
    ..The NCX1-G503P mutant that lacks Ca(2+)-dependent activation retained its sensitivity to PLM. We conclude that residues 248-252 and 300-304 in the proximal linker domain of NCX1 were involved in its inhibition by PLM...
  3. 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...
  4. pmc The transient receptor potential (TRP) channel TRPC3 TRP domain and AMP-activated protein kinase binding site are required for TRPC3 activation by erythropoietin
    Iwona Hirschler-Laszkiewicz
    Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 286:30636-46. 2011
    ..In particular, the TRPC3 C2 and AMPK site are essential for association of TRPC3 with the cytoskeleton and increased channel translocation to the cell surface in response to Epo stimulation...
  5. ncbi Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy
    Emanuele Giordano
    Department of Cellular and Molecular Physiology, The Penn State College of Medicine, Hershey, PA 17033 2390, USA
    Amino Acids 42:507-18. 2012
    ..Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility...
  6. pmc Cytosolic phospholipase A(2)α protects against ischemia/reperfusion injury in the heart
    Risto Kerkela
    Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Clin Transl Sci 4:236-42. 2011
    ..These studies are the first to identify a protective role for cPLA(2) in I/R injury in any organ and raise concerns over long-term inhibition of cPLA(2)...
  7. 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
    ....
  8. pmc Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity
    Tung O Chan
    Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Proc Natl Acad Sci U S A 108:E1120-7. 2011
    ..The lack of phosphatase resistance further contributes insight into the mechanism by which the human Akt2 R274H missense mutation may cause autosomal-dominant diabetes mellitus...
  9. pmc Constitutive overexpression of phosphomimetic phospholemman S68E mutant results in arrhythmias, early mortality, and heart failure: potential involvement of Na+/Ca2+ exchanger
    Jianliang Song
    Division of Nephrology, Thomas Jefferson Univ, 833 Chestnut St, Suite 700, Philadelphia, PA 19107, USA
    Am J Physiol Heart Circ Physiol 302:H770-81. 2012
    ..We conclude that constitutive overexpression of S68E mutant was detrimental, both in terms of depressed cardiac function and increased arrhythmogenesis...
  10. pmc Phospholemman deficiency in postinfarct hearts: enhanced contractility but increased mortality
    M Ayoub Mirza
    Cardiovascular Division, Department of Medicine, University of Virginia Medical Center, Charlottesville, Virginia, USA
    Clin Transl Sci 5:235-42. 2012
    ..Our findings indicate that alterations in PLM expression and phosphorylation are important adaptations post-MI, and that complete absence of PLM regulation of NKA and NCX1 is detrimental in post-MI animals...
  11. ncbi Coordinated regulation of cardiac Na(+)/Ca (2+) exchanger and Na (+)-K (+)-ATPase by phospholemman (FXYD1)
    Joseph Y Cheung
    Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Adv Exp Med Biol 961:175-90. 2013
    ..PLM regulates important ion transporters in the heart and offers a tempting target for development of drugs to treat heart failure...
  12. 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...
  13. pmc Role of TRPM2 in cell proliferation and susceptibility to oxidative stress
    Shu Jen Chen
    Department of Pediatrics, Pennsylvania State University College of Medicine, Milton S Hershey Medical Center, PO Box 850, Hershey, PA 17033, USA
    Am J Physiol Cell Physiol 304:C548-60. 2013
    ..TRPM2 channels may represent a novel future therapeutic target in diseases involving oxidative stress...
  14. pmc The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury
    Barbara A Miller
    Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA
    Am J Physiol Heart Circ Physiol 304:H1010-22. 2013
    ..We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress...
  15. pmc SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death
    Nicholas E Hoffman
    Department of Biochemistry, Temple University, Philadelphia, PA 19140 Center for Translational Medicine, Temple University, Philadelphia, PA 19140
    Mol Biol Cell 25:936-47. 2014
    ..Further, reconstitution with short hairpin RNA-insensitive SLC25A23 cDNA restores mitochondrial Ca(2+) uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca(2+) influx...
  16. pmc Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion
    Jufang Wang
    Center of Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
    Am J Physiol Heart Circ Physiol 306:H1066-77. 2014
    ..We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease...
  17. 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...
  18. pmc Regulation of in vivo cardiac contractility by phospholemman: role of Na+/Ca2+ exchange
    Jufang Wang
    Division of Nephrology and Center of Translational Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Am J Physiol Heart Circ Physiol 300:H859-68. 2011
    ..We conclude that under catecholamine stress when [Na(+)](i) is high, PLM minimizes [Na(+)](i) overload by relieving its inhibition of Na(+)-K(+)-ATPase and preserves inotropy by simultaneously inhibiting Na(+)/Ca(2+) exchanger...
  19. pmc Phospholemman inhibition of the cardiac Na+/Ca2+ exchanger. Role of phosphorylation
    Xue Qian Zhang
    Department of Cellular and Molecular Physiology, Milton S Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, USA
    J Biol Chem 281:7784-92. 2006
    ..By contrast, forskolin had no effect on I(NaCa) in wild-type myocytes. We conclude that PLM, when phosphorylated at serine 68, inhibits Na+/Ca2+ exchange in the heart...
  20. ncbi Regulation of the transient receptor potential channel TRPM2 by the Ca2+ sensor calmodulin
    Qin Tong
    Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 281:9076-85. 2006
    ..They suggest that Ca(2+) entering through TRPM2 enhances interaction of CaM with TRPM2 at the IQ-like motif in the N terminus, providing crucial positive feedback for channel activation...
  21. pmc Altered contractility and [Ca2+]i homeostasis in phospholemman-deficient murine myocytes: role of Na+/Ca2+ exchange
    Amy L Tucker
    Dept of Cellular and Molecular Physiology, Milton S Hershey Medical Center, MC H166, Hershey, PA 17003, USA
    Am J Physiol Heart Circ Physiol 291:H2199-209. 2006
    ..We conclude that a major function of PLM is regulation of cardiac contractility and Ca(2+) fluxes, likely by modulating Na(+)/Ca(2+) exchange activity...
  22. pmc Cytoplasmic tail of phospholemman interacts with the intracellular loop of the cardiac Na+/Ca2+ exchanger
    Jufang Wang
    Department of Cellular and Molecular Physiology, Milton S Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, USA
    J Biol Chem 281:32004-14. 2006
    ..We conclude that PLM interacted with the intracellular loop of NCX1, most likely at residues 218-358...
  23. ncbi Regulation of TRP channel TRPM2 by the tyrosine phosphatase PTPL1
    Wenyi Zhang
    Department of Pediatrics, The Pennsylvania State University College of Medicine, Milton S Hershey Medical Center, PO Box 850, Hershey, PA 17033, USA
    Am J Physiol Cell Physiol 292:C1746-58. 2007
    ..They also suggest that modulation of TRPM2 tyrosine phosphorylation is a mechanism through which PTPL1 may mediate resistance to cell death...
  24. ncbi Regulation of cardiac Na+/Ca2+ exchanger by phospholemman
    Joseph Y Cheung
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Ann N Y Acad Sci 1099:119-34. 2007
    ..This is in sharp contrast to the finding that the unphosphorylated PLM form inhibits Na+-K+-ATPase. We conclude that PLM regulates cardiac contractility by modulating the activities of NCX and Na+-K+-ATPase...
  25. doi Regulation of cardiac contractility: high time for FXYD
    Joseph Y Cheung
    Am J Physiol Heart Circ Physiol 294:H584-5. 2008
  26. pmc TRPC3 is the erythropoietin-regulated calcium channel in human erythroid cells
    Qin Tong
    Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 283:10385-95. 2008
    ..They also show that TRPC3 Tyr(226) is critical in Epo-dependent activation of TRPC3. These data demonstrate a redundancy of TRPC channel activation mechanisms by widely different agonists...
  27. pmc Regulation of cardiac myocyte contractility by phospholemman: Na+/Ca2+ exchange versus Na+ -K+ -ATPase
    Jianliang Song
    Division of Nephrology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    Am J Physiol Heart Circ Physiol 295:H1615-25. 2008
    ..We conclude that at the single-myocyte level, PLM affects cardiac contractility and [Ca(2+)](i) homeostasis primarily by its direct inhibitory effects on Na(+)/Ca(2+) exchange...
  28. pmc TRPC3 activation by erythropoietin is modulated by TRPC6
    Iwona Hirschler-Laszkiewicz
    Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 284:4567-81. 2009
    ..Endogenously, regulation of TRPC3 by TRPC6 may primarily be through modulation of signaling mechanisms, including reduced interaction of TRPC6 with phospholipase Cgamma and Epo-R...
  29. pmc Phospholemman regulates cardiac Na+/Ca2+ exchanger by interacting with the exchanger's proximal linker domain
    Xue Qian Zhang
    Division of Nephrology, Thomas Jefferson Univ, 833 Chestnut St, Suite 700, Philadelphia, PA 19107, USA
    Am J Physiol Cell Physiol 296:C911-21. 2009
    ..We conclude that PLM mediates its inhibition of NCX1 by interacting with residues 238-270 and 300-328...
  30. pmc Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration
    Jufang Wang
    Department of Medicine, Division of Nephrology, Center of Translational Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    Am J Physiol Heart Circ Physiol 297:H590-601. 2009
    ..In addition, heart failure did not occur 3 to 5 wk after NCX1 transgene was induced to be expressed at levels found in diseased hearts...
  31. pmc Phospholemman and beta-adrenergic stimulation in the heart
    Jufang Wang
    Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    Am J Physiol Heart Circ Physiol 298:H807-15. 2010
    ..We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist-mediated phosphorylation of PLM resulted in time-dependent reduction in inotropy due to relief of inhibition of Na(+)-K(+)-ATPase...
  32. pmc Effects of cardiac-restricted overexpression of the A(2A) adenosine receptor on adriamycin-induced cardiotoxicity
    Eman A Hamad
    Center for Translational Medicine, Dept of Medicine, Jefferson Medical College, 1025 Walnut St, Suite 822 College, Philadelphia, PA 19107, USA
    Am J Physiol Heart Circ Physiol 298:H1738-47. 2010
    ..Our data have direct relevance on the clinical use of adenosine agonists or antagonists in the treatment of patients undergoing adriamycin therapy...
  33. pmc Phospholemman: a novel cardiac stress protein
    Joseph Y Cheung
    Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Clin Transl Sci 3:189-96. 2010
    ..Clin Trans Sci 2010; Volume 3: 189-196...
  34. pmc TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria
    Barbara A Miller
    From the Center of Translational Medicine
    J Biol Chem 289:7615-29. 2014
    ..We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels. ..

Research Grants30

  1. Quantitative analysis of cAMP compartmentation in heart
    Jeffrey J Saucerman; Fiscal Year: 2013
    ..Indeed, the insights provided by this work will aid future efforts towards selectively targeting therapeutics to cardiac disease mechanisms, ultimately improving public health in the U.S. and abroad. ..
  2. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  3. Multi-scale Modeling of Calcium Mediated Triggered Activity in the Heart
    Yohannes Shiferaw; Fiscal Year: 2013
    ..Our computer models will shed light on the underlying mechanisms by bridging the gap between ion channels, cell electrophysiology, and tissue scale electrical activity. ..
  4. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  5. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  6. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  7. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  8. Regulatory Interactions of Cardiac Ion Pumps
    Seth L Robia; Fiscal Year: 2013
    ....
  9. GENE THERAPY FOR LONG-TERM MYOCARDIAL PROTECTION
    Victor J Dzau; Fiscal Year: 2013
    ..Public Health Relevance: This proposal is to study the mechanisms responsible for 2-catenin and ROR3t-regulated T cell apoptosis. ..
  10. 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. ..
  11. Cross-talk with the Insulin Receptor Attenuates Adrenergic Function within the He
    David Cervantes; Fiscal Year: 2013
    ..By elucidating the mechanism by which insulin attenuates adrenergic-mediated cardiac contractility both in vitro and in vivo, new therapeutic strategies may be developed to treat diabetic patients with heart failure. ..
  12. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  13. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  14. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  15. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..