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Role of the Phosphoprotein Phosphatase PTP1B in Cardiac Hypertrophy

Award Number: R15HL138605
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Role of the Phosphoprotein Phosphatase PTP1B in Cardiac Hypertrophy - Project Summary Cardiac hypertrophy occurs when cardiomyocytes are continuously exposed to stresses, such as mechanical stretch or neurohumoral stimulation. The enlargement is characterized by changes in signaling, gene expression and electrophysiology that confers short-term benefits; over time, however, the plasticity of the cardiac muscle in response to these pathological insults predispose individuals to heart failure and mortality. Hence, there is an urgent need to improve our understanding of the molecular events implicated in the development of cardiac hypertrophy and of the progression of heart failure in order to identify new therapeutic targets. Although numerous genetic and pharmacological studies have demonstrated that increased signaling by cellular oxidants were intimately involved in the progression of cardiac hypertrophy, the molecular mechanisms whereby oxidants contribute to the progression of hypertrophy are largely unknown. In order to shed light on these mechanisms, our efforts have focused on protein tyrosine phosphatases (PTPs) and their distinctive ability to be specifically and reversibly regulated by redox signaling. This research proposal builds upon our novel observations that oxidation and inactivation of protein tyrosine phosphatase 1B (PTP1B) leads to phosphorylation and inactivation of its substrate argonaute 2 (Ago2), a key mediator of the biological functions of microRNAs (miRNAs) in the hypertrophying myocardium. Preliminary data revealed in this proposal show that PTP1B inactivation by cellular oxidants and by conditional, cardiomyocyte-specific gene knockout (PTP1B cKO) results in phosphorylation and inactivation of its substrate Ago2, left ventricular hypertrophy and systolic dysfunction in a thyroid-hormone (T3)-dependent manner. Our in vivo data reveal an important relationship between PTP1B inactivation and T3 signaling in cardiac hypertrophy that occurs as a consequence of: defective miRNA-mediated repression of thyroid-hormone receptor-associated protein 1 (THRAP1, known as MED13); a miRNA-independent increase in thyroid-hormone receptor β1 (TRβ1) expression and; a TRβ1-interaction with p85 the regulatory subunit of phosphatidyl-inositol 3 kinase (PI3K) when PTP1B is inactivated. These data are consistent with the known T3 regulation of myocardial contractility and systolic function. We hypothesize that PTP1B inactivation prevents post-transcriptional regulation by Ago2-miR-208b and profoundly alters T3 signaling in cardiac hypertrophy. We propose that therapeutic compensation of PTP1B activity will be cardioprotective. We will test our hypothesis by investigating 1) the interplay between PTP1B and thyroid-hormone signaling in cardiac hypertrophy; 2) the therapeutic compensation of PTP1B activity in vivo. Understanding how PTP1B integrates redox signaling to regulate thyroid hormone signaling will facilitate the development of novel therapeutic strategies to control targeted protein expression and activation in cardiac pathologies.


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 = -$794 )
2024	2020	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	000	2	3/28/2024	COMPETING CONTINUATION	-$794
														Subtotal = -$794

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	000	2	9/9/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	001	2	6/23/2021	COMPETING CONTINUATION	$284
2021	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	000	1	6/23/2021	NEW	-$284
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $449,603 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	000	2	5/28/2020	COMPETING CONTINUATION	$449,603
														Subtotal = $449,603

Issue Date FY: 2017 ( Subtotal = $445,959 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cardiovascular Diseases Research	000	1	9/1/2017	NEW	$445,959
														Subtotal = $445,959

Grand Total All Awards = $894,768

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Role of the Phosphoprotein Phosphatase PTP1B in Cardiac Hypertrophy

Award Number: R15HL138605

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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