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Identifying new regulators of cardiac fibrosis and inflammation using zebrafish

Award Number: R01HL164749
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/22/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Identifying new regulators of cardiac fibrosis and inflammation using zebrafish - Project Summary/Abstract Several cardiac diseases involve the progressive or acute loss of cardiomyocytes, which are replaced by fibrotic tissue. Cardiac fibrosis is one of the leading factors in the pathology of heart failure, a progressive disease that affects millions of people every year. Despite its recognized importance, there are no effective therapies to prevent the progression of cardiac fibrosis. Recent findings suggest that naturally occurring genetic variants protect certain individuals against the adverse changes triggered after cardiac injury, which translates into re- duced cardiac fibrosis. One of the genes that modifies the progression of disease is the cardiomyocyte-specific kinase Tnni3k. Mutations that abolish Tnni3k confer resistance to injury, and high Tnni3k levels are associated with rapid functional decline and pathological remodeling. Tnni3k is an understudied kinase, and its downstream targets and specific mechanisms by which it defines injury outcome are unknown. Our goal in this project is to identify the mechanisms linking Tnni3k levels to cardiac fibrosis. In preliminary experiments using the zebrafish as a model, we found that high levels of Tnni3k induce fibrosis deposition shortly after cardiac injury. In contrast to their wild-type siblings, animals overexpressing Tnni3k showed impaired fibrotic regression, while a newly generated tnni3k mutant exhibits minimal fibrosis after injury. Transcriptional profiling revealed that high levels of Tnni3k correlate with an exacerbated inflammatory response, markers of T-cell infiltration, and activation of all the components of the inflammasome, which are all landmarks of cardiomyocyte-induced inflammation. We also identified a potential downstream target, itih5, which has been previously reported to play a role in extracel- lular matrix stabilization in the skin. Based on our preliminary results, our central hypothesis is that Tnni3k plays a previously unappreciated role in cardiac fibrosis via modulation of inflammation, and that Itih5 is a central mediator of these effects. We will test our hypothesis in three integrative aims. In Aim 1, we will determine the role of inflammation in the development of fibrosis in response to high levels of Tnni3k. We will exploit a collection of immunocompromised zebrafish to test the contribution of specific immune populations to this excessive fibrotic response. Additionally, we will use a new cardiomyocyte specific Cas9 line to identify genes required for trigger- ing inflammation in response to high Tnni3k levels. In Aim 2, we will determine the effects of modulating Tnni3k levels pre- and post-injury on cardiac fibrosis and inflammation. We will use a new Tnni3kSWITCH line generated by our lab that will allow us to “turn off” the overexpression of Tnni3k at different times. In Aim 3, we will identify molecular regulators of scar remodeling downstream of Tnni3k. We will start by analyzing how Itih5 regulates fibrosis regression using new gain and loss of function models generated by our laboratory for this application. Collectively, these studies will establish Tnni3k and Itih5 as regulators of cardiac inflammation and fibrosis in zebrafish. We anticipate that this basic knowledge will serve as the springboard for rapid discovery of new targets to treat cardiac fibrosis in the injured heart.


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 = $391,250 )
2024	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Cardiovascular Diseases Research	003	3	7/15/2024	NON-COMPETING CONTINUATION	$391,250
2024	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	11/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Cardiovascular Diseases Research	002	2	4/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$240,901
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	001	1	4/11/2024	NEW	-$240,901
														Subtotal = $391,250

Issue Date FY: 2023 ( Subtotal = $391,250 )
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Cardiovascular Diseases Research	001	2	8/22/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$391,250
2023	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	8/18/2023	NEW	$0
														Subtotal = $391,250

Issue Date FY: 2022 ( Subtotal = $420,000 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	8/12/2022	NEW	$420,000
														Subtotal = $420,000

Grand Total All Awards = $1,202,500

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Identifying new regulators of cardiac fibrosis and inflammation using zebrafish

Award Number: R01HL164749

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/22/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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