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The Role of TGF-beta Activation and Signaling in Aortic Stenosis Progression

Award Number: R01HL148123
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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The Role of TGF-beta Activation and Signaling in Aortic Stenosis Progression - PROJECT SUMMARY Aortic stenosis (AS) is a complex multifactorial disease. Delayed diagnosis of this disorder is a leading cause of morbidity and mortality due to heart failure. Undiagnosed AS is often associated with aortic regurgitation (AS/AR), a mixed aortic valve disease with a poor prognosis due to accelerated heart failure compared to patients with AS alone. We previously observed that laminar shear stress (LSS), such as that found in AS, can activate up to 5% of the total latent TGFβ1 (LTGFβ1) released from platelets in vitro. When we examined LA100 mice (LDLR- knockout mice expressing ApoB100), a murine model that spontaneously develops AS, we found that platelet TGFβ1 contributes to AS progression. Despite this progress, the molecular mechanism by which shear activates LTGFβ1 is not clearly understood because the amount of active TGFβ1 generated in these models was insufficient for assessment of biochemical changes. We have recently developed a new model that generates more LTGFβ1 activation. We found an association of anemia with AS severity in patients older than 75 years and in LA100 mice older than 65 weeks. Creating anemia in LA100 mice produces oscillatory shear stress (OSS), accelerates AS, and induces aortic regurgitation (AS/AR). AS/AR mice have higher levels of active TGFβ1 and TGFβRI intracellular domain (ICD) signaling in valvular cells, with accelerated heart failure and acquired von Willebrand syndrome (AVWS) than AS only mice. In vitro, OSS induced >20% LTGFβ1 activation, 4-fold higher than that generated by LSS, as well as disulfide-bonded complex formation between LTGFβ1 and vWf. Correcting anemia with iron supplementation normalized elevated TGFβ1 levels, and partial inhibition of TGFβ signaling prevented AS progression in LA100 mice. These results indicate that our new AS/AR and OSS model generates much higher force and more LTGFβ1 activation than LSS in mice with AS alone, associated with accelerated disease progression. We propose to: (1) Determine how anemia and OSS accelerate LTGFβ1 activation and drive AS/AR and heart failure progression using in vitro biochemical assays and a more robust model of LA100 plus anemia to assess whether correcting anemia or blocking OSS-induced LTGFβ1 activation prevents disease progression; (2) Determine how TGFβ signaling via the ICD pathway affects gene transcription in valvular cells, including infiltrating neutrophils. We will employ spatial transcriptomics with MERFISH and Cut&Run. We will also partially block TGFβ signaling with low dose galunisertib and compare its effect with other known inhibitors of fibrosis, pirfenidone and dapagliflozin, in preventing fibrosis and disease progression. Additionally, we will test sensitive techniques to evaluate TGFβ1 levels and AVWS in our preclinical model, and to determine their potential value as biomarkers for prognosis as we test a mitigation strategy for correcting anemia and blocking TGFβ signaling with galunisertib. These studies will contribute to our understanding of OSS-dependent LTGFβ1 activation and signaling and may establish them as treatment targets for AS/AR, heart failure, and potentially a range of fibrotic diseases.


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 = $786,750 )
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	5	8/21/2026	COMPETING CONTINUATION	$786,750
														Subtotal = $786,750

Issue Date FY: 2025 ( Subtotal = -$9,368 )
2025	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	6/25/2025	NON-COMPETING CONTINUATION	-$9,368
														Subtotal = -$9,368

Issue Date FY: 2023 ( Subtotal = $517,430 )
2023	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	2/8/2023	NON-COMPETING CONTINUATION	$517,430
														Subtotal = $517,430

Issue Date FY: 2022 ( Subtotal = $523,299 )
2022	2022	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	001	3	5/31/2022	NON-COMPETING CONTINUATION	$52,333
2022	2022	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	3	2/11/2022	NON-COMPETING CONTINUATION	$470,966
														Subtotal = $523,299

Issue Date FY: 2021 ( Subtotal = $523,846 )
2021	2021	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	2	3/5/2021	NON-COMPETING CONTINUATION	$523,846
														Subtotal = $523,846

Issue Date FY: 2020 ( Subtotal = $523,846 )
2020	2020	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	1	3/29/2020	NEW	$523,846
														Subtotal = $523,846

Grand Total All Awards = $2,865,803

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The Role of TGF-beta Activation and Signaling in Aortic Stenosis Progression

Award Number: R01HL148123

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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