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CALCIUM PUMP NITRATION AND INHIBITION OF CALCIUM TRANSPORT IN THE AGING HEART

Award Number: R15HL091410
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2008
PERIOD OF PERFORMANCE END DATE: 12/31/2010

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CALCIUM PUMP NITRATION AND INHIBITION OF CALCIUM TRANSPORT IN THE AGING HEART - DESCRIPTION (provided by applicant): The Ca2+ translocating ATPase (i.e., the Ca2+ pump) is an integral membrane enzyme that transports Ca2+ ions into the sarcoplasmic reticulum (SR) to promote muscle relaxation. In cardiac muscle, the Ca2+ pump is regulated by phospholamban (PLB), and this regulation is relieved by PLB phosphorylation. During normal aging, Ca2+ pump activity declines resulting in prolonged Ca2+ transients and slowed cardiac muscle relaxation rates. In addition to other well defined age-based changes in Ca2+ pump function, the Ca2+ pump is progressively nitrated at specific tyrosine residues during aging, and studies of the isolated enzyme suggest tyrosine nitration correlates directly with Ca2+ transport inhibition. However, the mechanism of Ca2+ pump inhibition following nitration is not understood, so a role for calcium pump nitration in age-based loss of calcium pump function cannot be supported or refuted. Therefore, the objective of this application is to determine the physical and kinetic mechanisms by which Ca2+ pump nitration leads to the inhibition of Ca2+ pump transport activity. Our hypothesis is that Ca2+ pump nitration shifts the enzyme toward the low energy, Ca2+ affinity Ca2+ pump state (the E2 intermediate) relative to the high affinity, Ca2+-activated Ca2+ pump state (the E1 intermediate), and inhibits the kinetic transitions between the two enzyme intermediate states. Because PLB interacts most strongly with the E2 state, we also propose that PLB will be a more potent inhibitor of the nitrated Ca2+ pump. To test these hypotheses and their alternatives, we will combine kinetic studies of the Ca2+ transport cycle (Aim 1) and spectroscopic studies of Ca2+ pump conformational changes during the Ca2+ transport cycle (Aim 2) to determine the physical mechanism of Ca2+ pump inhibition due to nitration. For these studies, we will use native cardiac SR vesicles obtained from young adult (6 month old) rats versus senescent (24 month old) rats, which contain different amounts of endogenously nitrated Ca2+ pump. The specific role of Ca2+ pump nitration in physical and kinetic differences between the two sample types will be further explored by conducting additional studies on Ca2+ pump from the young animals pre-treated with peroxynitrite to mimic progressive age-based Ca2+ pump nitration. The results of this project will define or reject a role for Ca2+ pump nitrotyrosine formation in the loss of Ca2+ transport activity with age. More generally, the project will provide a foundation for future studies designed to test strategies for the prevention and/or treatment of age-based loss of cardiac Ca2+ transport function due to oxidative damage to the Ca2+ pump.


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: 2010 ( Subtotal = $0 )
2010	2008	EDWARD VIA VA COLLEGE OF OSTEOPATHIC MEDICINE	2265 KRAFT DRIVE	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	11/9/2009	NEW	$0
2010	2008	EDWARD VIA VA COLLEGE OF OSTEOPATHIC MEDICINE	2265 KRAFT DRIVE	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	001	1	1/8/2010	NEW	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $221,145 )
2008	2008	EDWARD VIA VA COLLEGE OF OSTEOPATHIC MEDICINE	2265 KRAFT DRIVE	BLACKSBURG	VA	24060	MONTGOMERY	USA	Academic Research Enhancement Award	000	1	12/26/2007	NEW	$221,145
														Subtotal = $221,145

Grand Total All Awards = $221,145

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CALCIUM PUMP NITRATION AND INHIBITION OF CALCIUM TRANSPORT IN THE AGING HEART

Award Number: R15HL091410

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2008

PERIOD OF PERFORMANCE END DATE: 12/31/2010

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