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C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure

Award Number: R01HL127691
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure - Project Title: C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Heart Failure Project Summary Myocardial contractility is essential for cardiac function. Troponin-mediated thin myofilament regulation controls cardiac muscle contraction and relaxation. The troponin complex consists of three protein subunits: the calcium receptor troponin C (TnC), the inhibitory subunit troponin I (TnI), and the tropomyosin-binding subunit troponin T (TnT). Cardiac TnI plays a pivotal role in myofilament activation and deactivation, determining the kinetics of cardiac muscle contraction and relaxation, and pumping efficiency of the heart. Our research project focuses on a novel therapeutic peptide derived from the conserved C-terminal end mobile domain of cardiac TnI (cTnI-C27) for its effect on enhancing myocardial relaxation and the underlying mechanisms. Biochemical, genetic and physiological approaches and mouse models of diastolic cardiac dysfunction are employed to study cTnI-C27 peptide to understand its selective enhancement of diastolic function of the heart. The ultimate goal is to develop a targeted treatment for diastolic heart failure (HFpEF) that presently lacks an effective treatment. Three Specific Aims are proposed in the research plan: Aim 1 is to characterize the mechanism for exogenous cTnI-C27 peptide to modulate myofilament function as an activated state-specific myofilament Ca2+- desensitizer. We shall determine the binding site of cTnI-C27 peptide on tropomyosin in thin filament and characterize its effect on contractile kinetics and endogenous troponin regulation of myofibril actomyosin ATPase in reconstituted myofilaments and skinned cardiac muscle. The results will determine how exogenous cTnI-C27 peptide modulates cardiac muscle contractility, especially the enhanceing of Frank-Starling response without increasing sarcomere length. Aim 2 is to study the delivery of cTnI-C27 peptide into cardiomyocytes for functional effect. Heart-homing fusion peptide, AAV9 and inducible transgenic expression of cTnI-C27 peptide will be studied in vivo and in ex vivo working hearts. Effects on cardiac muscle contractility and heart function will be examined for therapeutic efficacy in normal and diastolic dysfunctional and fibrotic mouse hearts to evaluate the therapeutic potential of cTnI-C27 peptide. Aim 3 is to determine the chronic effects of exogenous cTnI-C27 peptide on cardiac function and remodeling. To develop the cTnI-C27 peptide for the treatment of chronic heart failure, we need to understand the effects of chronic presence of cTnI-C27 peptide on cardiac muscle. We shall examine the therapeutic and side-effects of chronic transgenic expression of cTnI-C27 peptide in normal and failing mouse heart. In vivo and ex vivo cardiac function, tolerance to hemodynamic stresses, and myocardial remodeling will be examined in young and aging mice to collect informative longitudinal data. With combined expertise in myofilament protein structure-function relationships and cardiac physiology and pathophysiology using multi-level experimental approaches, the study of a promising therapeutic peptide of endogenous origin will lay mechanistic and methodologic groundwork for translating a novel myofilament mechanism into a new treatment for diastolic 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: 2026 ( Subtotal = $399,750 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	9	3/19/2026	NON-COMPETING CONTINUATION	$399,750
2026	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	8	3/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $399,750

Issue Date FY: 2025 ( Subtotal = $399,750 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	8	5/7/2025	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2024 ( Subtotal = $399,750 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	7	3/4/2024	NON-COMPETING CONTINUATION	$399,750
2024	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	5	9/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $399,750

Issue Date FY: 2023 ( Subtotal = $680,934 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	6	8/22/2023	SUPPLEMENT FOR EXPANSION	$281,184
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	6	3/10/2023	COMPETING CONTINUATION	$399,750
														Subtotal = $680,934

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	5	3/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$1 )
2021	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	4	5/5/2021	NON-COMPETING CONTINUATION	-$140,449
2021	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	002	4	7/30/2021	NON-COMPETING CONTINUATION	$0
2021	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	5	5/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$140,448
														Subtotal = -$1

Issue Date FY: 2019 ( Subtotal = $386,450 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	4	3/21/2019	NON-COMPETING CONTINUATION	$386,450
														Subtotal = $386,450

Issue Date FY: 2018 ( Subtotal = $386,450 )
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	001	3	7/6/2018	NON-COMPETING CONTINUATION	$7,729
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	3	3/30/2018	NON-COMPETING CONTINUATION	$378,721
														Subtotal = $386,450

Issue Date FY: 2017 ( Subtotal = $386,450 )
2017	2017	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	2	3/29/2017	NON-COMPETING CONTINUATION	$386,450
														Subtotal = $386,450

Issue Date FY: 2016 ( Subtotal = $411,450 )
2016	2016	WAYNE STATE UNIVERSITY	5700 CASS SUITE 4602	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	1	4/21/2016	NEW	$411,450
														Subtotal = $411,450

Grand Total All Awards = $3,450,983

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C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure

Award Number: R01HL127691

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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