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TROPONIN AND MYOSIN IN REGULATION OF MUSCLE CONTRACTION AND HEART DISEASE

Award Number: R01HL091162
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2008
PERIOD OF PERFORMANCE END DATE: 03/01/2013

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TROPONIN AND MYOSIN IN REGULATION OF MUSCLE CONTRACTION AND HEART DISEASE - A number of familial hypertrophic cardiomyopathy (FHC) causing mutations have been identified in the regulatory proteins, tropomyosin (Tm) and troponin (Tn). Most of these mutations cause an increase in the Ca2+-sensitivity of muscle contraction, i.e. the onset of force occurs at lower Ca2+ concentrations. Neither the molecular mechanisms underlying the increased Ca2+-sensitivity nor its relation to the hypertrophy of the heart are well understood. Stretch activation is another cardiac phenomenon whose molecular mechanism is not understood. The long-range goal is to understand the molecular basis of FHC and stretch activation. The main hypothesis that we will test is that both of these activations involve strongly bound cross bridges (myosin heads). We plan to: 1. Determine the contribution of the myosin head-induced vs. Ca2+-induced changes in the interactions of troponin I (TnI) with actin-Tm and with troponin C (TnC) in thin filaments reconstituted with skeletal and cardiac muscle isoforms of the regulatory proteins. The main techniques will be solution ATPase and FRET measurements. 2. Determine effects of FHC mutations on occupancy of the 3 thin filament regulatory states using equilibrium titrations and transient kinetics. Fluorescent labels on selected proteins will be used to obtain equilibrium constants and rates. 3. Determine effects of selected FHC mutations in TnI and Tm on ATPase in terms of myosin vs. Ca2+ activation. FRET measurements will be used to obtain structural information. 4. Test the hypothesis that the C-terminal domain of TnC is involved in the myosin head induced activation of the thin filament. Mutants of TnC having increased affinity for Mg2+ will be used to assess the role of divalent cation in the C-domain of TnC on thin filament function. A novel mutant of TnC which reconstitutes into the thin filament and binds Ca2+ but does not activate ATPase that was developed in this lab will be used. These experiments will lead to a better understanding of the regulatory mechanism in cardiac and skeletal muscle. In particular, a better understanding of the relative contribution of the Ca2+/troponin-dependent and the myosin S1/actin-dependent activation of the thin filament will be obtained. By identifying the protein-protein interactions that are altered in the disease state it will be possible to suggest potential targets for drug design for FHC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	000	4	3/21/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $502,425 )
2012	2012	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	001	4	4/3/2012	NON-COMPETING CONTINUATION	$50,242
2012	2012	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	000	4	11/21/2011	NON-COMPETING CONTINUATION	$452,183
														Subtotal = $502,425

Issue Date FY: 2011 ( Subtotal = $507,500 )
2011	2011	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	11/19/2010	NON-COMPETING CONTINUATION	$507,500
														Subtotal = $507,500

Issue Date FY: 2010 ( Subtotal = $507,500 )
2010	2010	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	11/27/2009	NON-COMPETING CONTINUATION	$507,500
														Subtotal = $507,500

Issue Date FY: 2009 ( Subtotal = $507,500 )
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Cardiovascular Diseases Research	000	1	12/8/2008	NEW	$507,500
														Subtotal = $507,500

Grand Total All Awards = $2,024,925

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TROPONIN AND MYOSIN IN REGULATION OF MUSCLE CONTRACTION AND HEART DISEASE

Award Number: R01HL091162

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2008

PERIOD OF PERFORMANCE END DATE: 03/01/2013

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