[R01] The Role of TGF-beta Activation and Signaling in Aortic Stenosis Progression
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-06-30
Importo max: 786.750 EUR
Paese: US
Descrizione
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
Istituzione: OKLAHOMA MEDICAL RESEARCH FOUNDATION
PI: Jasimuddin Ahamed
Progetto: 2R01HL148123-05A1
Settori: National Heart Lung and Blood Institute
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