TROPONIN MODULATION IN HEART FAILURE
M Beata
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 5R01HL064035-13 from National Heart, Lung, And Blood Institute
Keywords: Address; Adverse effects; Affect; Animal Model; Attenuated; Blood; Calcium; Cardiac; Cardiomyopathies; Cardiomyopathy, Hypertrophic, Familial; Complex; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; desensitization; design; Development; Diagnostic; Equilibrium; Figs - dietary; Functional disorder; Funding; Health; Heart; Heart Diseases; Heart failure; Hypertrophic Cardiomyopathy; Hypertrophy; In Situ; In Vitro; insight; Investigation; Knowledge; Lead; Link; Lipids; MAP Kinase Gene; MAPK14 gene; Medicine; Microfilaments; Modification; mouse model; Mutation; myosin-binding protein C; novel; p21 activated kinase; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; pressure; prevent; Protein Dephosphorylation; Protein phosphatase; Proteins; Publishing; receptor; Recording of previous events; Regulation; Relative (related person); research study; response; rho; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Site; Sphingomyelins; Testing; Therapeutic; Therapeutic Intervention; therapeutic target; tool; Transgenic Mice; Translating; Translations; Tropomyosin; Troponin; Troponin I; Troponin T
Relevance: Experiments proposed in the present application determine a new mechanism for control of the pressure developed in the heart that is responsible for ejection of blood. The new mechanism is likely to add to our understanding of heart failure, when pressure and ejection of blood is disturbed. Moreover, the new mechanism may lead to development of novel therapies for heart failure
Project start date: 2000-01-15
Project end date: 2013-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01HL064035-13 (2012): $349718
Sponsored Links Excellgen http://Excellgen.com
TROPONIN MODULATION IN HEART FAILURE
M Beata, Professor And Head
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 5R01HL064035-12 from National Heart, Lung, And Blood Institute
Abstract: In experiments proposed here we test the hypothesis that signaling through p21 activated kinase (Pak1) to protein phosphatase 2A (PP2A) is a novel mechanism of control of contractility by suppression of Ca-release units (CRU) in excitation contraction coupling (ECC) via effects on Ca2+ channel and ryanodine receptor function and stimulation of myofilament response to Ca2+ via sarcomeric protein dephosphorylation. Preliminary and published data in the current period of funding indicate that the function of Pak1 in integrated control of contractility involves signaling through 2-receptor/PKA phosphorylation of Pak1 and through sphingomyelin related lipid signaling that also activates Pak1. We also identified a novel mechanism of regulation of sarcomeric protein phosphorylation by various active forms of PKC6, which also acts in a signaling complex with Pak1. Aim #1 of our proposals is to test the hypothesis that the Pak1-PP2A signaling cascade is a novel mechanism of control of contractility acting by regulating the balance of CRU activity in ECC and myofilament response to Ca2+. Aim #2 is to determine the functional significance of diverse pathways of activation of PKC6 that induce dephosphorylation of cTnI and cTnT and phosphorylation of MyBP- C and Tm. Aim # 3 extends our studies on novel control of myofilament response to Ca2+ to our objective to determine if specific desensitization of the myofilaments to Ca2+ can serve as a therapeutic tool to prevent or attenuate the development of hypertrophy and dysfunction in transgenic mouse models of familial hypertrophic cardiomyopathy (HCM). Our preliminary and published data indicate that desensitization of myofilament response to calcium is able to rescue adverse effects in HCM-linked sarcomeric mutations in mouse models. Results of experiments proposed will provide insights into a previously unappreciated mode of activation of contractility, which provides new leads in translation medicine in cardiomyopathies. Experiments proposed in the present application determine a new mechanism for control of the pressure developed in the heart that is responsible for ejection of blood. The new mechanism is likely to add to our understanding of heart failure, when pressure and ejection of blood is disturbed. Moreover, the new mechanism may lead to development of novel therapies for heart failure
Keywords: Actin Filaments; Address; Adenosine Cyclic Monophosphate-Dependent Protein Kinases; Adverse effects; Affect; Animal Model; Animal Models and Related Studies; Asymmetric Septal Hypertrophy, Familial; Attenuated; balance; balance function; biological signal transduction; Blood; Blood Coagulation Factor IV; Ca Release Channel-Ryanodine Receptor; Ca++ element; Calcium; Calcium-Ryanodine Receptor Complex; cAMP-Dependent Protein Kinases; Cardiac; Cardiac Diseases; Cardiac Disorders; cardiac failure; Cardiomyopathies; Cardiomyopathy, Hypertrophic Obstructive; Cardiomyopathy, Hypertrophic, Familial; Cell Communication and Signaling; Cell Signaling; Coagulation Factor IV; Complex; Coupling; CSBP1; CSBP2; CSPB1; Cyclic AMP-Dependent Protein Kinases; Data; Dephosphorylation; desensitization; design; designing; Development; Diagnostic; Dysfunction; EC 2.7; Equilibrium; EXIP; experiment; experimental research; experimental study; Extracellular Signal-Regulated Kinase Gene; Factor IV; Figs; Figs - dietary; Functional disorder; Funding; gene product; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Heart; Heart Diseases; heart disorder; Heart failure; heavy metal lead; heavy metal Pb; History; HTRPY; Hypertrophic Cardiomyopathy; hypertrophic myocardiopathy; Hypertrophy; In Situ; In Vitro; inhibitory troponin I; insight; intervention therapy; Intracellular Communication and Signaling; Investigation; Kinases; Knowledge; language translation; Lead; Link; Lipids; MAP Kinase Gene; MAPK; MAPK14; MAPK14 gene; Medicine; Microfilaments; Mitogen-Activated Protein Kinase Gene; model organism; Modification; mouse model; Mutation; Mxi2; MyBP-C protein; Mycocardium Disease; Myocardial Diseases; Myocardial Disorder; Myocardiopathies; myocardium disorder; Myofilaments; myosin-binding protein C; novel; p21 activated kinase; p38; p38 MAPK Gene; p38Alpha; pathophysiology; pathway; Pathway interactions; Pb element; Phosphatases; Phosphohydrolases; Phosphomonoesterases; Phosphoprotein Phosphatase; Phosphoprotein Phosphatase-2C; Phosphoprotein Phosphohydrolase; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiopathology; PKA; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; pressure; Pressure; Pressure- physical agent; prevent; preventing; PRKM14; PRKM15; Protein Dephosphorylation; Protein Kinase A; Protein Modification; Protein Modification, Post-Translational; Protein phosphatase; Protein Phosphatase C; Protein Phosphatase-1; Protein Phosphatase-2A; Protein Phosphorylation; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; public health relevance; Publishing; receptor; receptor function; Receptor Protein; Recording of previous events; Regulation; Relative; Relative (related person); research study; response; Reticuloendothelial System, Blood; rho; Ryanodine Receptor; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; SAPK2A; Science of Medicine; side effect; Signal Transduction; Signal Transduction Systems; Signaling; Site; Sphingomyelins; Testing; Therapeutic; Therapeutic Intervention; therapeutic target; therapy adverse effect; TnI; TNT; tool; Transgenic Mice; Translating; Translatings; Translations; Transphosphorylases; treatment adverse effect; Treatment Side Effects; Tropomyosin; tropomyosin binding protein troponin T; Troponin; Troponin I; Troponin T; Ventricular Hypertrophy, Familial
Relevance: Experiments proposed in the present application determine a new mechanism for control of the pressure developed in the heart that is responsible for ejection of blood. The new mechanism is likely to add to our understanding of heart failure, when pressure and ejection of blood is disturbed. Moreover, the new mechanism may lead to development of novel therapies for heart failure
Project start date: 2000-01-15
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01HL064035-12 (2011): $392500