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The overall goal of this part of the laboratory’s program is to integrate specific signaling pathways with cardiac and cardiomyocyte function in the adult and during development, emphasizing the pathological implications of aberrant signaling and resultant stress on the cardiomyocyte. The laboratory uses the general approach of targeted mutagenesis along with cardiac-specific loss- and gain-of-function approaches, which can be modulated precisely. Each project is driven by specific hypotheses and experiments so that these methodologies are appropriate. Since the modifications can be controlled in a tissue and even cardiac-compartment-specific fashion, as well as at different developmental times, very precise genetic manipulations can be carried out effectively.
The cardiac-specific gain-of-function approach is particularly powerful if coupled with the use of inducible systems and a novel and robust, cardiac-specific inducible promoter, developed in the Robbins laboratory. A comprehensive analysis of the resultant mice can be a daunting task for a single lab, both in terms of time and expense, but the use of divisional cores greatly enhances the cost-effectiveness of the research. The Histopathology / Physiology Core provides a coherent centralized facility for generating cytological analyses where gross or subtle manifestations of the pathology or cytopathology resulting from the various targeting experiments can be discerned, integrated, and valuable correlations made between the different projects. Integration of these data directly with physiology aids in their integrative interpretation as well as pointing the way to the next experiments in order to extend the descriptive data into mechanism and function. The lab also has the capability of studying the entire functional spectrum of the modified cells, organ or whole animals, using a variety of invasive and noninvasive techniques, while another core provides a common source of cells suitable for transfection as well as the necessary adenovirus constructs and stocks.
A particular focus of the lab is the sarcomeric protein known as myosin binding protein C (MyBP-C). This is one of the most frequently mutated proteins found in human familial hypertrophic cardiomyopathy (FHC) and these alleles exhibit autosomal dominance. It is not clear as to whether the ensuing pathology is due to functional haploinsufficiency, the action(s) of a poison peptide or some combination. Complicating an understanding of the role or roles of truncated forms of cMyBP are our recent data showing the production of a stable 29kD fragment from cMyBP-C as a result of ischemia reperfusion injury and / or general cardiovascular stress. The fragment is stable but its functional capacity is unknown. Preliminary data indicate that it retains a capacity to influence contractile function, leading us to hypothesize that cMyBP-C fragments can play an important role in determining cardiomyocyte functionality.
Our objective is to explicitly define the functional and mechanistic outcomes of a series of cMyBP-C truncations that cause disease, and compare those data with the data obtained using the 29kD cMyBP-C fragment that is endogenously produced under stressed conditions. The central hypothesis is that while haploinsufficiency may play a role in the pathology of some of these mutations, a majority function as poison peptides, possibly through depression of thick-thin filament cycling. We are testing the hypothesis that the 29kD cMyBP-C fragment can function as a poison peptide by actively interfering with normal thick-thin filament interaction. Using a combination of isolated systems, in vitro cell culture and developmental stage-specific transgenesis, the function of this fragment will be determined. We are also testing the hypothesis that cMyBP-C truncations lead to pathology through haploinsufficiency or, more frequently, production of a poison peptide. A series of cMyBP-C’s carrying nonsense codons defined as causing human FHC will be made and used to replace endogenous cMyBP-C. The impact of the mutations on the cardiomyocyte’s general stress response and ensuing pathology will be determined and the pathogenic mechanism(s) determined.
Gupta MK, Robbins J. Post-translational control of cardiac hemodynamics through myosin binding protein C. Pflugers Arch. 2014 Feb;466(2):231-6.
Mun JY, Previs MJ, Yu HY, Gulick J, Tobacman LS, Beck Previs S, Robbins J, Warshaw DM, Craig R. Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2170-5.
Alves ML, Dias FA, Gaffin RD, Simon JN, Montminy EM, Biesiadecki BJ, Hinken AC, Warren CM, Utter MS, Davis RT, 3rd, Sadayappan S, Robbins J, Wieczorek DF, Solaro RJ, Wolska BM. Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins. Circ Cardiovasc Genet. 2014 Apr 1;7(2):132-43.
Liu Y, Lu X, Xiang FL, Poelmann RE, Gittenberger-de Groot AC, Robbins J, Feng Q. Nitric oxide synthase-3 deficiency results in hypoplastic coronary arteries and postnatal myocardial infarction. Eur Heart J. 2014 Apr;35(14):920-31.
Dhandapany PS, Razzaque MA, Muthusami U, Kunnoth S, Edwards JJ, Mulero-Navarro S, Riess I, Pardo S, Sheng J, Rani DS, Rani B, Govindaraj P, Flex E, Yokota T, Furutani M, Nishizawa T, Nakanishi T, Robbins J, Limongelli G, Hajjar RJ, Lebeche D, Bahl A, Khullar M, Rathinavel A, Sadler KC, Tartaglia M, Matsuoka R, Thangaraj K, Gelb BD. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet. 2014 Jun;46(6):635-9.
Tanner BC, Wang Y, Robbins J, Palmer BM. Kinetics of cardiac myosin isoforms in mouse myocardium are affected differently by presence of myosin binding protein-C. J Muscle Res Cell Motil. 2014 Dec;35(5-6):267-78.
Huby A, Mendsaikhan U, Takagi K, Martherus R, Wansapura J, Gong N, Osinska H, James JF, Kramer K, Saito K, Robbins J, Khuchua Z, Towbin JA, Purevjav E. Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. J Amer Coll Cardiol. 2014 Dec 30;64(25):2765-76.
Michalek AJ, Howarth JW, Gulick J, Previs MJ, Robbins J, Rosevear, PR, Warshaw DM. Phosphorylation modulates mechanical stability of the cardiac myosin binding protein C motif. Biophysical J. 2013 Jan 22;104(2):442-52.
Wang Y, Tanner, BC Lombardo, AT, Tremble SM, Maughan, DW, VanBuren, P, LeWinter, MM, Robbins, J, Palmer B. Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity. J Mol Cell Cardiol. 2013 Jan;54:1-8.
Liu Y, Lu X, Xiang F, Poelman RE, Gittenberger-de Groot AC, Robbins J, Feng Q. Nitric oxide synthase-3 deficiency results in hypoplastic coronary arteries and post-natal myocardial infarction. Eur Heart J. 2014 Apr;35(14):920-31.
Hinken AC, Hanft LM, Scruggs SB, Sadayappan S, Robbins J, Solaro RJ, McDonald KS. Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A. J Muscle Res Cell Motil. 2012 Dec;33(6):439-48.
Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Blair NS, Lynch KA, Aronow B, Osinska O, Prywes R, Lorenz JN, Lawler J, Robbins J. A thrombospondin-dependent pathway for a protective ER stress response. Cell. 2012 149(6):1257-68
Previs MJ, Previs SB, Gulick J, Robbins J, Warshaw DM. Molecular mechanics of cardiac myosin binding protein C in native thick filaments. Science. 2012 337(6099):1215-18.
Weith A, Sadayappan S, Gulick J, Previs MJ, Vanburen P, Robbins J, Warshaw DM. Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain. J Mol Cell Cardiol. 2012;52:219-227.
Jeyaraj D, Haldar SM, Wan X, McCauley MD, Ripperger JA Lu Y, Eapen BL, Ficker E, Cutler MJ, Gulick J, Sanbe,A, Robbins,J, Brandimarto J, Cappola TP, Margulies KB, Kondratov RV, Shea SA, Albrecht you, Weherens KHT, Demolomve S, Rosenblum D, Jain MK. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature. 2012 483(7387):96-9.
Sciarretta, S, Zhai, P, Shao, D, Maejima, Y, Robbins, J, Volpe, M, Condorelli G, Sadoshima J. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation. 2012 125:(9) 1134-1146.
Bhuiyan MS, Gulick J, Osinska O, Gupta M, Robbins J. Determination of the critical residues responsible for cardiac myosin binding protein C’s interactions. J Mol Cell Cardiol. 2012 Dec;53(6):838-47.
Haghighi K, Pritchard T, Bossuyt J, Waggoner JR, Yuan Q, Fan GC, Osinska H, Anjak A, Rubinstein J, Robbins J, Bers DM, Kranias EG. The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. J Mol Cell Cardiol. 2011 52(3):773-82.
Tranter M, Liu Y, He S, Gulick J, Robbins J, Jones WK. Poly(glycoamidoamine)-mediated delivery of NF-κB oligodeoxynucleotide decoys affords therapeutic infarct size reduction in vivo. Mol Therapy. 2011 20(3):601-8.
James J, Robbins J. At the source: treating heart failure by altering muscle motor function. Circ Res. 2011 Jun 24;109(1):5-7.
James J, Robbins J. Signaling and myosin-binding protein C. J Biol Chem. 2011 Mar 25;286(12):9913-9.
Li J, Horak KM, Su H, Sanbe A, Robbins J, Wang X. Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest. 2011 Sep 1;121(9):3689-700.
Li X, Chan TO, Myers V, Chowdhury I, Zhang XQ, Song J, Zhang J, Andrel J, Funakoshi H, Robbins J, Koch WJ, Hyslop T, Cheung JY, Feldman AM. Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Galphaq-mediated cell signaling. Circulation. 2011 Aug 2;124(5):572-81.
McLendon PM, Robbins J. Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1220-8.
Mun JY, Gulick J, Robbins J, Woodhead J, Lehman W, Craig R. Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C). J Mol Biol. 2011 Jul 8;410(2):214-25.
Palmer BM, Sadayappan S, Wang Y, Weith AE, Previs MJ, Bekyarova T, Irving TC, Robbins J, Maughan DW. Roles for cardiac MyBP-C in maintaining myofilament lattice rigidity and prolonging myosin cross-bridge lifetime. Biophys J. 2011 Oct 5;101(7):1661-9.
Robbins J. Twenty years of gene targeting: what we don't know. Circ Res. 2011 Sep 16;109(7):722-3.
Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J. A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res. 2011 Jul 8;109(2):141-50.
Stanley BA, Graham DR, James J, Mitsak M, Tarwater PM, Robbins J, Van Eyk JE. Altered myofilament stoichiometry in response to heart failure in a cardioprotective alpha-myosin heavy chain transgenic rabbit model. Proteomics Clin Appl. 2011 Apr;5(3-4):147-58.
Maillet M, Davis J, Auger-Messier M, York A, Osinska H, Piquereau J, Lorenz JN, Robbins J, Ventura-Clapier R, Molkentin JD. Heart-specific deletion of CnB1 reveals multiple mechanisms whereby calcineurin regulates cardiac growth and function. J Biol Chem. 2010 Feb 26;285(9):6716-24.
Maloyan A, Robbins J. Autophagy in desmin-related cardiomyopathy: Thoughts at the halfway point. Autophagy. 2010 Jul 1;6(5).
Maloyan A, Sayegh J, Osinska H, Chua BH, Robbins J. Manipulation of death pathways in desmin-related cardiomyopathy. Circ Res. 2010 May 14;106(9):1524-32.
James J, Hor K, Moga MA, Martin L, Robbins J. Effects of myosin heavy chain manipulation in experimental heart failure. J Mol Cell Cardiology. 2010 May;48(5):999-1006.
Heineke J, Wollert KC, Osinska H, Sargent M, York AJ, Robbins J, Molkentin J. Calcineurin protects the heart in a murine model of dilated cardiomyopathy. J Mol Cell Cardiology. 2010 Jun;48(6):1080-7.
Terrell D, Robbins J. Protein conformation-based disease: getting to the heart of the matter. Annual Review Physiol. 2010;72:15-7.
Bardswell SC, Cuello F, Rowland A, Sadayappan S, Robbins J, Gautel M, Walker JW, Kentish JC, Avkirin M. Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and crossbridge cycling. J Biol Chem. 2010 Feb 19;285(8):5674-82.
Nakamura T, Gulick J, Colbert MC, Robbins J. Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development. Proc Natl Acad Sci, U S A. 2009 Jul 7;106(27):11270-5.
Nakamura T, Gulick J, Pratt R, Robbins J. Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proc Natl Acad Sci, U S A. 2009;106: 15436-15441.
Maloyan A, Osinska H, Lammerding J, Lee RT, Cingolani OH, Kass D, Lorenz JN, Robbins J. Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy. Circ Res. 2009;104: 1021-1028.
Xiang F-L, Hammoud L, Robbins J, Feng Q. Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice. Circulation. 2009;120: 1065-1074.
Itoh H, MacGillivray C,Kwon H-S, Lammerding J, Robbins J, Lee R, So P. Three-dimensional cardiac architecture determined by two-photon microtomy. J Biomedical Optics. 2009 Jul-Aug;14(4):044029.
Nicolaou P, Rodriguez P, Zhou X, Ren X, Qian J, Sadayappan S, Mitton B, Pathak A, Robbins J, Hajjar R, Jones K, Kranias EG. Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemic/reperfusion injury. Circ Res. 2009;104: 1012-1020.
Suzuki T, Palmer BM, James J, Yuan Wang Y, Chen Z, VanBuren P, Maughan DW, Robbins J, LeWinter MM. Effects of cardiac myosin isoform variation on myofilament function and crossbridge kinetics in transgenic rabbits. Circulation, Heart Failure. 2009 Jul;2(4):334-41.
Sadayappan S, Klevitsky R, Lorenz JN, Sargent M, Gulick J, Molkentin JD, Robbins J. Cardiac myosin binding protein-C phosphorylation in a beta-myosin heavy chain background. Circulation. 2009;119: 1253-1262.
Scruggs SB, Hinken AC, Thawornkaiwong A, Robbins J, Walker LA, de Tombe P, Geenen D. L, Buttrick PM, Solaro RJ. Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation. J Biol Chem. 2009;285: 5097-5106.
Wu X, Blair NS, Sargent M, York AJ, Robbins J, Shull G, Molkentin JD. Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents. J Clin Invest. 2009;119: 976-985.
Waggoner J, Ginsburg K, Bersohn M, Mitton B, Haghighi K, Robbins J, Bers D, Kranias E. Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport. Am J Physiol. 2009;296: H698-703.
Gulick J, Robbins J. Cell-type specific transgenesis in the mouse. Methods in Molecular Biology. 2009;561: 91-106.
Krenz M, Gulick J, Osinska HE, Colbert MC, Molkentin JD, Robbins J. Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome. Proc Natl Acad Sci, U S A. 2008;105: 18930-18936.
Pinz I, Ostroy SE, Hoyer K, Osinska H, Robbins J, Molkentin JD, Ingwall JS. Calcineurin-induced energy wasting in a transgenic mouse model of heart failure. Am J Physiol Heart Circ Physiol. 2008;294: H1459-1466.
Molkentin J, Robbins J. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. JMCC. 2008;46:130-136.
Moga MA, Nakamura T, Robbins J. Genetic approaches for changing the heart. JMCC. 2008;45:148-155.
Yano N, Tseng A, Zhao TC, Robbins J, Padbury J, Tseng YT. Temporally controlled overexpression of cardiac-specific PI3Kalpha induces enhanced myocardial contractility — a new transgenic model. Am J Physiol Heart Circ Physiol. 2008;295:1690-1694.
Lowey S, Lesko LM, Rovner AS, Hodges AR, White SL, Low RB, Gulick J, Robbins J. Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone. J Biol Chem. 2008;283:20579-2089.
Sadayappan S, Finley N, Howarth J W, Osinska H, Klevitsky R, Lorenz JN, Rosevear PR, JG, Robbins J. Role of the acidic N’ region of cardiac troponin I in regulating myocardial function. FASEB Journal. 2008;22:1246-1257.
Sadayappan S, Robbins J. The death of transcriptional chauvinism in the control and regulation of cardiac contractility. NY Acad Sci. 2008 Mar;1123:1-9.
Pattison JS, Waggoner JR, James J, Martin L, Gulick J, Osinska H, Klevitsky R, Kranias EG, Robbins J. Phospholamban overexpression in transgenic rabbits. Transgenic Res. 2008;17:157-170.
Wolf CM, Arad M, Ahmad F, Sanbe A, Bernstein SA, Toka O, Morley G, Robbins J, Seidman JG, Seidman CE, Berul CI. Reversibility of PRKAG2 glycogen storage cardiomyopathy and electrophysiologic manifestations. Circulation. 2008;117:144-154.
Pinz I, Robbins J, Benjamin IJ, Ingwall J. Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPB2 using genetically modified mouse hearts. FASEB J. 2008;22: 84-92.
Krenz M, Sadayappan S, Osinska HE, Henry JA, Beck S, Warshaw DM, Robbins J. Distribution and structure-function relationship of myosin heavy chain isoforms in the adult mouse heart. J Biol. Chem. 2007;282: 24057-24064.
Hambleton M, York A, Sargent MA, Kaiser RA, Lorenz JN, Robbins J, Molkentin JD. Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure. Am J Physiol Heart Circ Physiol. 2007;293: H3768-H3771.
Nagyama T, Takimoto E, Sadayappan S, Mudd JO, Seidman JG, Robbins J, Kass DA. Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation. 2007;116: 2399-2408.
Diwan A, Krenz M, Sayed FM, Wanasapura J, Ren X, Matkovich SJ, Koesters AG, Li H, Kirshenbaum LA, Robbins J, Jones WK, Dorn GW 2nd. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of bnip3 restrains post-infarction remodeling. J Clin Invest. 2007;117: 2825-2833.
Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, Lorts A, Brunskill EW, Dorn GW 2nd, Conway SJ, Aronow BJ, Robbins J, Molkentin JD. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ Res. 2007;101:313-321.
Nakamura T, Colbert M, Krenz M, Molkentin JD, Hahn HS, Dorn GW 2nd, Robbins J. Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J Clin Invest. 2007;117:2123-2132.
Hsieh PCH, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nature Med. 2007;13, 970-974.
Yasuda S-I, Coutu P, Sadayappan S, Robbins J, Metzger JM. Cardiac transgenic and gene transfer strategies converge to support an important role for troponin I in regulating relaxation in cardiac myocytes. Circ Res. 2007;101:377-386.
Purcell NH, Wilkins BJ, York A, Robbins J, Molkentin J. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc. Natl Acad Sci U S A. 2007;104, 14074-14079.
Galvez AS,Diwan A, Odley AM, Hahn HS, Osinska H, Melendez JG, Robbins J,Lynch RA, Marreez Y, Dorn GW. Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ Res. 2007;100, 1071-1078.
Nishizawa T, Shen Y-T, Rossi F, Hong C, Robbins J, Ishikawa J, Sadoshima J, Vatner D, Vatner S. Altered autonomic control in conscious transgenic rabbits with overexpressed cardiac Gsa. Am J Physiol. 2007;292, H971-975.
Hoyer K, Krenz M, Robbins J, Ingwall JS. Shifts in the myosin heavy chain isozymes in the mouse heart result in increased energy efficiency. J Mol Cell Cardiol. 2007;42, 214-221.
Yutzey KE, Robbins J. Principles of genetic murine models for cardiac disease. Circulation. 2007;115:792-799.
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