Tuesday, September 16, 2025 9/16/2025

Fibroblast TAK1 signaling in cardiac fibrosis

Award Number: F30HL165813
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 12/30/2026

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Fibroblast TAK1 signaling in cardiac fibrosis - Abstract Cardiovascular diseases share fibrosis as a common characteristic. Fibrosis is caused in large part by activation of cardiac fibroblasts, which change their phenotype in response to insults such as pressure overload or myocardial infarction and contribute to excessive deposition of extracellular matrix (ECM) in the myocardial interstitium and perivascular space. Previous studies in models of cardiac fibrosis demonstrate that elevated levels of paracrine factors such as TGF-β are fundamental in fibroblast activation. In particular, activation of the canonical TGF-β/Smad pathway is known to play a prominent role in cardiac fibrosis; however, the response of cardiac fibroblasts to stress also involves paracrine signaling by other ligands elevated in the injured or stressed heart. Indeed, inflammatory cytokines such as TNF-α and IL-1β also contribute to changes fibroblast phenotype. Signaling elicited by these ligands appear to target signaling pathways that converge on TGF-β-activated kinase 1 (TAK1), which is known to integrate signals from not only TNF-α and IL-1β receptors, but TGF-β receptors as well. Our preliminary data suggest that TAK1 is abundant in cardiac fibroblasts and that its inhibition influences the expression of key markers of the myofibroblast phenotype. Moreover, our data suggest that deletion of TAK1 in cardiac fibroblasts influences the secretion of profibrotic cytokines and proteins, which further intimates a critical role of TAK1 in fibroblast phenotype and fibrosis. Guided by these findings, we hypothesize that TAK1 integrates cytokine and growth factor signaling to modulate the response of cardiac fibroblasts to insult or injury. Although it is likely that fibroblast TAK1 signaling plays a major role in cardiac fibrosis, there have been no detailed studies that elucidate its influence on fibroblast-mediated myocardial responses to stress. This knowledge is important because it could be used to develop targeted strategies to lessen fibrotic burden in the heart, for which there are currently no approved therapies. To test our hypothesis, we will: (1) assess the influence of TAK1 on cardiac fibroblast phenotype; and (2) elucidate the role of fibroblast-specific TAK1 on pressure overload-induced cardiac remodeling. Completion of this project will delineate how non-canonical fibrotic signaling through TAK1 influences cardiac remodeling and fibrosis in models of fibroblast activation and pressure overload. We expect to find that TAK1 acts as a central nexus that integrates profibrotic signals to promote cardiac fibrosis. Such knowledge is important because it will not only enhance our understanding of mechanisms of cardiac fibrosis, but also could be used to develop new therapeutic avenues to diminish fibrotic burden in the heart. Working with my sponsors and clinical mentors, I will develop a better understanding of the mechanisms that promote cardiac fibrosis and refine my critical thinking skills, which will enhance my success in biomedical research and as a clinician.


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 = $54,538 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	9/2/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	8/19/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $34,484 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	8/21/2023	NEW	$34,484
														Subtotal = $34,484

Grand Total All Awards = $142,996

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Fibroblast TAK1 signaling in cardiac fibrosis

Award Number: F30HL165813

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 12/30/2026

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