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Novel Mechanisms of Cardiac Function and Dysfunction

Award Number: R01HL143074
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Novel Mechanisms of Cardiac Function and Dysfunction - While the cardiac kinome is comprised of several hundred kinases, the vast majority of the literature is focused on only a few kinases. Indeed, the function of numerous highly expressed cardiac kinases, many of which may be potential therapeutic targets, are unexplored. In order to identify novel cardiac kinase(s) potentially involved in HF development, we employed a combined transcriptome and bioinformatics approach (Expression2Kinases (X2K)). This integrated approach enabled us to discover the critical role of serine-threonine kinase Homeodomain-Interacting Protein Kinase 2 (HIPK2) in cardiomyocyte (CM) biology. Specifically, we employed three different mouse models and AAV9-mediated gene therapy approaches to define the CM-specific role of HIPK2 and underlying mechanisms. Since there was no literature connecting HIPK2 to cardiac biology, these studies were entirely novel. HIPK2 has been strongly implicated in multiple organ fibrosis. However, the role of HIPK2 in fibrotic remodeling of the ischemic heart is entirely unknown. Herein, we aim to define the role of HIPK2 in adult heart fibroblast (FB) biology and fibrotic remodeling in the ischemic heart. As a first step towards this goal, we have generated inducible conditional FB-specific mouse models (FB-HIPK2-KOs driven by periostinMCM and TCF21MCM). Our preliminary studies suggest that FB-specific deletion of HIPK2 leads to excessive fibrosis and accelerated cardiac dysfunction post-MI. At the cellular/molecular level, adenovirus-mediated expression of HIPK2 (Ad-HIPK2) reduced the pro-fibrotic TGF-β1-mediated SMAD-2/3 activation and myofibroblasts transformation. Therefore, we hypothesize that HIPK2 exerts a critical break on fibrotic remodeling by inhibiting the canonical TGF-β1-SMAD-3 signaling. The preliminary data strongly support our overall hypothesis that HIPK2 is a critical negative regulator of FB activation and adverse myocardial fibrotic remodeling in the diseased heart. Specific aims are designed to critically examine the role of HIPK2 in cardiac FB biology and fibrotic remodeling of the ischemic heart. The proposed PeriostinMCM and TCF21MCM models are widely accepted as the strongest tools available for FB-specific in vivo gene targeting. Furthermore, throughout the proposal, a wide range of in vitro assays have been incorporated to gain mechanistic insights into the in vivo findings. Thus, the proposed studies are of high significance, not only by contributing translationally-relevant information to manage ischemic cardiac injury but also by providing novel mechanistic insights into cardiac pathophysiology.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	2/24/2025	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	2/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $544,035 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	5/21/2024	COMPETING CONTINUATION	$544,035
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	5/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $544,035

Issue Date FY: 2022 ( Subtotal = $462,111 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	8/8/2022	NON-COMPETING CONTINUATION	$462,111
														Subtotal = $462,111

Issue Date FY: 2021 ( Subtotal = $458,029 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	8/11/2021	NON-COMPETING CONTINUATION	$458,029
														Subtotal = $458,029

Issue Date FY: 2020 ( Subtotal = $428,783 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	9/4/2020	NON-COMPETING CONTINUATION	$428,783
														Subtotal = $428,783

Issue Date FY: 2019 ( Subtotal = $425,571 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	1	9/20/2019	NEW	$0
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	9/18/2019	NEW	$425,571
														Subtotal = $425,571

Grand Total All Awards = $2,318,529

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Novel Mechanisms of Cardiac Function and Dysfunction

Award Number: R01HL143074

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/18/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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