Modulation of Ca Control of Cardiac Myofibrils

Summary

Principal Investigator: R John Solaro
Abstract: DESCRIPTION (provided by applicant): Our long term goal in experiments proposed here is to identify the mechanism(s) responsible for the down-regulation of the slow skeletal troponin I (ssTnI) isoform, which occurs during post-natal maturation of the heart. Preliminary data underpin our hypothesis that the microRNA, miR-208a, is involved in silencing the cardiac expression of ssTnI after birth. Our experiments continue research supported by this proposal that demonstrated that expression of ssTnI in the adult heart of transgenic mice protects the myocardium against common stresses including familial dilated cardiomyopathy (DCM). Preliminary data demonstrate: i) increased expression of miR-208a with muscle specific miRs, miR-1 and miR-133a in developing cardiomyocytes, and ii) knockdown of miR-208a in cardiomyocytes by a 208a-antagomiR induces ssTnI expression. Our objectives are as follows: Aim #1 To determine mechanism(s) of ssTnI and miR-208a mediated regulation by (a) investigating interplay of miR-208a with thyroid hormone mediated down regulation of ssTnI, (b) analyzing the role of miR-208a in conjunction with other co-regulated miRNAs in ssTnI gene regulation, (c) investigating transcriptional mechanisms of ssTnI gene regulation, and (d) evaluating ssTnI as a direct target of miRNA- mediated regulation. Aim #2: To determine the relative impact of miR-208a KO on modifications of thin filament proteins, on myofilament response to Ca, on myocyte mechanics and Ca, and on in situ cardiac function. Aim #3. To determine whether reduced expression of miR-208a improves cardiac function in dilated cardiomyopathy (DCM) associated with an alpha-tropomyosin mutation. Our approach to Aim #1 includes i) analysis of expression of ssTnI in neonatal cardiac myocytes by gain and loss of function approaches to dissect the relative significance of thyroid related signaling in the repression of ssTnI;ii) determination the relative role of miR-208a as a repressor of ssTnI expression employing co-induction with other miRs;iii) identification of transcription factors targeted by miR-208a and determination of their DNA binding and expression;and iv) identification of targets of miR-208a in ssTnI 3'UTR. Our approaches to Aims #2 include studies comparing miR208a-KO mice to controls to determine the functional impact of altered myofilament properties as reflected in isoform population, post-translational modifications, pCa-force relations and cross- bridge kinetics. Findings from studies of skinned myocytes are integrated into myocardial function by studies of Ca2+ transients and mechanics at the level of cardiac myocytes and of dynamics of in situ beating hearts responding to stresses including those dominated by altered thin filament properties. In Aim #3 our approach is to determine whether cross-breeding a familial DCM mouse model linked to a tropomyosin mutation with the miR208a-KO mouse is able to rescue the DCM phenotype. Experiments proposed here fill a significant gap in our understanding of the control of expression of the isoform population of myocardial TnI, an essential thin filament protein, and test a significant therapeutic approach to cardiac disorders.
Funding Period: 2011-08-18 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death
    Sumeyye Yar
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, M C 901, Chicago, IL, 60612, USA
    Pflugers Arch 466:1189-97. 2014
  2. pmc Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation
    Chehade N Karam
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave M C 901, Chicago, IL 60612 7342, USA
    J Muscle Res Cell Motil 31:315-22. 2011
  3. pmc Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis
    Katherine A Sheehan
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Mol Cell Cardiol 50:442-50. 2011
  4. pmc Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy
    James R Pena
    Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Mol Cell Cardiol 49:993-1002. 2010
  5. pmc Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Albert B Sabin Way, Cincinnati, OH 45267 0524, USA
    J Muscle Res Cell Motil 31:227-39. 2010
  6. pmc H2O2 alters rat cardiac sarcomere function and protein phosphorylation through redox signaling
    Benjamin S Avner
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612 7342, USA
    Am J Physiol Heart Circ Physiol 299:H723-30. 2010
  7. pmc Sarcomere control mechanisms and the dynamics of the cardiac cycle
    R John Solaro
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612, USA
    J Biomed Biotechnol 2010:105648. 2010
  8. pmc A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain
    Sarah B Scruggs
    Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612, USA
    Mol Cell Proteomics 9:1804-18. 2010
  9. pmc The significance of regulatory light chain phosphorylation in cardiac physiology
    Sarah B Scruggs
    University of California Los Angeles, Department of Physiology, Division of Cardiology, 90095, USA
    Arch Biochem Biophys 510:129-34. 2011
  10. pmc Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia
    Kayla M Pound
    Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    J Mol Cell Cardiol 51:236-43. 2011

Detail Information

Publications46

  1. pmc Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death
    Sumeyye Yar
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, M C 901, Chicago, IL, 60612, USA
    Pflugers Arch 466:1189-97. 2014
    ..We think that these new perspectives provide a rationale for future studies directed at a more thorough understanding of the question driving our review. ..
  2. pmc Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation
    Chehade N Karam
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave M C 901, Chicago, IL 60612 7342, USA
    J Muscle Res Cell Motil 31:315-22. 2011
    ..Our results identify a novel mode of myofilament desensitization to Ca(2+) associated with a DCM linked switch in TM isoform population...
  3. pmc Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis
    Katherine A Sheehan
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Mol Cell Cardiol 50:442-50. 2011
    ....
  4. pmc Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy
    James R Pena
    Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Mol Cell Cardiol 49:993-1002. 2010
    ..Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth...
  5. pmc Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Albert B Sabin Way, Cincinnati, OH 45267 0524, USA
    J Muscle Res Cell Motil 31:227-39. 2010
    ..This is significant in relation to current ideas on the control mechanism of the steep relation between Ca(2+) and tension...
  6. pmc H2O2 alters rat cardiac sarcomere function and protein phosphorylation through redox signaling
    Benjamin S Avner
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612 7342, USA
    Am J Physiol Heart Circ Physiol 299:H723-30. 2010
    ..These data provide evidence that PKC-dependent redox signaling affects the function of cardiac myofilaments and indicate modification of specific proteins through this signaling mechanism...
  7. pmc Sarcomere control mechanisms and the dynamics of the cardiac cycle
    R John Solaro
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612, USA
    J Biomed Biotechnol 2010:105648. 2010
    ..Application of these ideas to translational medicine and rationale drug design forms an important rationale for detailed understanding of these processes...
  8. pmc A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain
    Sarah B Scruggs
    Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612, USA
    Mol Cell Proteomics 9:1804-18. 2010
    ....
  9. pmc The significance of regulatory light chain phosphorylation in cardiac physiology
    Sarah B Scruggs
    University of California Los Angeles, Department of Physiology, Division of Cardiology, 90095, USA
    Arch Biochem Biophys 510:129-34. 2011
    ..Data demonstrating altered levels of RLC phosphorylation in comparisons of samples from normal and stressed human hearts indicate the significance of these findings in translational medicine...
  10. pmc Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia
    Kayla M Pound
    Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    J Mol Cell Cardiol 51:236-43. 2011
    ..This article is part of a Special Issue entitled "Possible Editorial"...
  11. pmc Influence of a constitutive increase in myofilament Ca(2+)-sensitivity on Ca(2+)-fluxes and contraction of mouse heart ventricular myocytes
    Jose L Puglisi
    Department of Pharmacology, University of California Davis, Davis, CA 95616, United States
    Arch Biochem Biophys 552:50-9. 2014
    ..This modification may be of significance in early changes in altered gene expression and electrical stability hearts with increased myofilament Ca-sensitivity. ..
  12. pmc A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling
    Raghu S Nagalingam
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 288:11216-32. 2013
    ..Our study demonstrates that miR-378 is an endogenous negative regulator of Ras signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy...
  13. pmc Integration of troponin I phosphorylation with cardiac regulatory networks
    R John Solaro
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    Circ Res 112:355-66. 2013
    ..We review how phosphorylation signaling to cardiac troponin I is integrated, with parallel signals controlling excitation-contraction coupling, hypertrophy, and metabolism...
  14. pmc Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties
    Euy Myoung Jeong
    Department of Medicine, Section of Cardiology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    J Mol Cell Cardiol 56:44-54. 2013
    ..These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins...
  15. pmc Tropomyosin Ser-283 pseudo-phosphorylation slows myofibril relaxation
    Benjamin R Nixon
    Department of Physiology and Cell Biology and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States
    Arch Biochem Biophys 535:30-8. 2013
    ..This supports a role for Tm as a key protein in the regulation of muscle relaxation dynamics...
  16. pmc New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I
    Marcus Henze
    Department of Physiology and Biophysics, University of Illinois, Chicago, IL 60612, USA
    Biochim Biophys Acta 1833:823-32. 2013
    ..This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction...
  17. pmc Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A
    Aaron C Hinken
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    J Muscle Res Cell Motil 33:439-48. 2012
    ....
  18. pmc AMP-activated protein kinase phosphorylates cardiac troponin I at Ser-150 to increase myofilament calcium sensitivity and blunt PKA-dependent function
    Benjamin R Nixon
    Department of Physiology and Cell Biology and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 287:19136-47. 2012
    ....
  19. pmc A novel cardiomyocyte-enriched microRNA, miR-378, targets insulin-like growth factor 1 receptor: implications in postnatal cardiac remodeling and cell survival
    Ivana Knezevic
    Department of Physiology and Biophysics, and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 287:12913-26. 2012
    ..We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R, and IGF1 that is associated with postnatal cardiac remodeling and with the regulation of cardiomyocyte survival during stress...
  20. pmc Removal of the cardiac troponin I N-terminal extension improves cardiac function in aged mice
    Brandon J Biesiadecki
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 285:19688-98. 2010
    ....
  21. pmc Sub-proteomic fractionation, iTRAQ, and OFFGEL-LC-MS/MS approaches to cardiac proteomics
    Chad M Warren
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Proteomics 73:1551-61. 2010
    ..Our workflow provides an approach for discovery of unique biomarkers or changes in the protein profile of tissue in disorders of the heart...
  22. pmc Cardiac thin filament regulation
    Tomoyoshi Kobayashi
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
    Pflugers Arch 457:37-46. 2008
    ..Here, we review current knowledge regarding protein-protein interactions involved in the dynamics of thin filament activation and relaxation and the regulation of these processes by protein kinase-mediated phosphorylation...
  23. pmc Increased cross-bridge cycling kinetics after exchange of C-terminal truncated troponin I in skinned rat cardiac muscle
    Kittipong Tachampa
    Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois, Chicago, IL 60612, USA
    J Biol Chem 283:15114-21. 2008
    ..Decreased cardiac function after ischemia/reperfusion injury may directly result, in part, from proteolytic degradation of cTnI, resulting in alterations in cross-bridge cycling kinetics...
  24. doi Review focus series: sarcomeric proteins as key elements in integrated control of cardiac function
    R John Solaro
    Cardiovasc Res 77:616-8. 2008
  25. pmc The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation
    R John Solaro
    Department of Physiology and Biophysics M C901 and Center for Cardiovascular Research, 835 South Wolcott Avenue, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    Biochem Biophys Res Commun 369:82-7. 2008
    ..A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I...
  26. pmc Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant (Glu54Lys) linked to dilated cardiomyopathy
    Chad M Warren
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 E Wolcott Avenue, Chicago, IL 60612, USA
    Proteomics 8:100-5. 2008
    ....
  27. ncbi Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity
    Sudarsan Rajan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267 0524, USA
    Circ Res 101:205-14. 2007
    ..As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM...
  28. ncbi Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0524, USA
    Am J Physiol Heart Circ Physiol 293:H949-58. 2007
    ..These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease...
  29. ncbi Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells
    Yunbo Ke
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA
    Circ Res 100:1317-27. 2007
    ..In conclusion, our data demonstrate that a Pak1 signaling pathway exists in cardiac pacemaker cells and that this novel pathway plays a role in the regulation of ion channel activity...
  30. pmc Effects of thin and thick filament proteins on calcium binding and exchange with cardiac troponin C
    Jonathan P Davis
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210, USA
    Biophys J 92:3195-206. 2007
    ..These results imply that both cross-bridge kinetics and Ca(2+) dissociation from troponin C work together to modulate the rate of cardiac muscle relaxation...
  31. pmc Quantitative comparison of sarcomeric phosphoproteomes of neonatal and adult rat hearts
    Chao Yuan
    Department of Physiology and Biophysics, UIC, Chicago, IL 60612, USA
    Am J Physiol Heart Circ Physiol 295:H647-56. 2008
    ....
  32. pmc Multiplex kinase signaling modifies cardiac function at the level of sarcomeric proteins
    R John Solaro
    Department of Physiology and Biophysics and the Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 283:26829-33. 2008
  33. pmc Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation
    Sarah B Scruggs
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Biol Chem 284:5097-106. 2009
    ..Our data also indicate that the lack of RLC phosphorylation promotes compensatory changes in MyBP-C and TnI phosphorylation, which when normalized do not restore function...
  34. pmc Why does troponin I have so many phosphorylation sites? Fact and fancy
    R John Solaro
    Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Center for Cardiovascular Research, Chicago, IL 60612, USA
    J Mol Cell Cardiol 48:810-6. 2010
    ..Moreover, we agree that the changes and effects of cTnI phosphorylation need to be fully integrated into the effects of other phosphorylations in the cardiac myocyte...
  35. pmc Phosphorylation of cardiac troponin I at protein kinase C site threonine 144 depresses cooperative activation of thin filaments
    Qun Wei Lu
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Biol Chem 285:11810-7. 2010
    ..These data highlight the importance of thin filament-based cooperative mechanisms in cardiac regulation, with implications for mechanisms of control of function in normal and pathological hearts...
  36. pmc PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation
    Dong I Lee
    Ross 858, Division of Cardiology, Department of Medicine, Johns Hopkins University Medical Institutions, Baltimore, MD, 21205, USA
    Basic Res Cardiol 105:337-47. 2010
    ..These data support a cascade involving beta3-AR stimulation, and subsequent PKG-dependent TnI S23, S24 phosphorylation as primary factors underlying the capacity of acute PDE5A inhibition to blunt myocardial beta-adrenergic stimulation...
  37. pmc Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform
    Sudarsan Rajan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267 0524, USA
    Circulation 121:410-8. 2010
    ..Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear...
  38. pmc An internal domain of beta-tropomyosin increases myofilament Ca(2+) sensitivity
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0524, USA
    Am J Physiol Heart Circ Physiol 297:H181-90. 2009
    ..Furthermore, these results enhance the understanding of why TM mutations associated with familial hypertrophic cardiomyopathy demonstrate increased myofilament sensitivity to Ca(2+)...
  39. pmc Differential effects of phosphorylation of regions of troponin I in modifying cooperative activation of cardiac thin filaments
    Patti L Engel
    Department of Physiology and Biophysics M C 901, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612, USA
    J Mol Cell Cardiol 47:359-64. 2009
    ..Although these effects of PKC dependent phosphorylation may be maladaptive in heart failure, they may also spare ATP consumption and be cardio-protective in ischemia...
  40. pmc Regulation of cardiac excitation and contraction by p21 activated kinase-1
    Yunbo Ke
    The Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Room 202, COMRB, 835 South Wolcott Avenue, Chicago, IL 60612, USA
    Prog Biophys Mol Biol 98:238-50. 2008
    ..Coordination of Pak1 and PP2A activities is not only potentially involved in regulation of normal cardiac function, but is likely to be important in patho-physiological conditions...
  41. ncbi Development and cardiac contractility: cardiac troponin T isoforms and cytosolic calcium in rabbit
    Shannon J McCall
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
    Pediatr Res 60:276-81. 2006
    ..2 +/- 1.6 pA/pF). The higher calcium sensitivity of Tn-Ca binding and of force development conferred by rcTnT(1) suggest that higher neonatal cTnT(1) expression may partially compensate for the lower systolic [Ca(2+)](i)...

Research Grants30

  1. Signaling of Endothelial Permeability and Lung Vascular Injury
    Asrar B Malik; Fiscal Year: 2013
    ..Moreover the depth of understanding to be gained of the signaling pathways mediating the increase in lung vascular permeability will provide novel insights into the mechanisms of protein-rich pulmonary edema and ARDS. ..
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  3. Inflammatory-metabolic Crosstalk in the Myocardium
    JOEL DAVID SCHILLING; Fiscal Year: 2013
    ..This proposal will evaluate how the inflammatory response affects the heart and how it may contribute to the heart failure that develops in diabetic patients. ..
  4. Connexin Distribution in Physiological Versus Pathological Cardiac Hypertrophy
    Michael R Zile; Fiscal Year: 2013
    ..pathological hypertrophy, with ex- tensively characterized cytoskeletal properties in each setting. ..
  5. Myosin ELC, a novel therapeutic target for FHC
    Danuta Szczesna-Cordary; Fiscal Year: 2013
    ..These studies will help to determine the role(s) of the ELC and the N-terminal cardiac specific ELC extension in the regulation of contractile force in healthy and FHC-diseased hearts. ..
  6. Cardiac Stem Cells and Angiomyogenesis
    Jan Kajstura; Fiscal Year: 2013
    ....
  7. YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration
    WILLIAM TSWENCHING PU; Fiscal Year: 2013
    ..Successful execution of these aims will inform efforts to improve heart function and stimulate myocardial regeneration. ..
  8. A new post-translational modification, citrullination, changes in heart failure
    Jennifer E Van Eyk; Fiscal Year: 2013
    ..This work will lead to understanding of an entirely new mechanism for post-translational protein regulation in the heart. ..
  9. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  10. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  11. Kinetics of Cardiac Myofilament Activation
    Wen Ji Dong; Fiscal Year: 2013
    ..This application is related to research to improve depressed cardiac contractility under pathological conditions. ..
  12. Titin-based adaptations of cardiac function
    Henk L Granzier; Fiscal Year: 2013
    ....
  13. 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. ..