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Role of Protein Tyrosine Phosphatase 1B in Cardiac Hypertrophy

Award Number: R01HL175391
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Role of Protein Tyrosine Phosphatase 1B in Cardiac Hypertrophy - Project Summary Oxidative stress is associated with reduced left ventricular (LV) function and correlates with the severity of heart failure in patients. We have recently demonstrated that Protein Tyrosine Phosphatase 1B (PTP1B) becomes reversibly oxidized and inactivated in pressure overload-induced cardiac hypertrophy and that PTP1B inactivation causes profound changes in thyroid hormone responsiveness. We showed that inhibiting the synthesis of triiodothyronine (T3) rescued the exacerbated pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in cardiomyocyte-specific PTP1B knockout mice (PTP1B cKO). We hypothesize that as hypertrophy develops, the inhibition of the cardioprotective activity of PTP1B by cellular oxidants leads to T3-mediated changes contributing to pathological hypertrophy. Based on our recently published data in which we demonstrate that breaking the interaction between 14-3-3ζ and PTP1B prevents its inactivation in vivo, we also hypothesize that ectopic expression of a peptide derived from PTP1B, will both prevent the oxidation and inactivation of PTP1B in myocytes, and prevent pathological thyroid hormone signaling, left ventricular hypertrophy and heart failure. We propose the following specific aims to test this hypothesis.1) Determine the molecular mechanisms controlling PTP1B oxidation and downstream thyroid hormone signaling in cardiac hypertrophy. 2) Investigate the potential therapeutic and anti-hypertrophic effects of a novel PTP1B peptide that destabilizes the oxidized form of PTP1B and increases its catalytic activity in vivo. Understanding how PTP1B regulates thyroid hormone-mediated hypertrophy will provide critical insight into molecular mechanisms involved in cardiac hypertrophy and lead to novel strategies of therapeutic intervention in heart failure.


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: 2024 ( Subtotal = $566,357 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cardiovascular Diseases Research	000	1	6/11/2024	NEW	$566,357
														Subtotal = $566,357

Grand Total All Awards = $566,357

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Role of Protein Tyrosine Phosphatase 1B in Cardiac Hypertrophy

Award Number: R01HL175391

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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