[R01] Hydrogel matrices to study the role of inflammation and biological sex on aortic valve fibrocalcification
Ente: National Heart Lung and Blood Institute
Scadenza: 2028-04-30
Importo max: 637.519 EUR
Paese: US
Descrizione
ABSTRACT
Thirteen percent of adults over 75 suffer from aortic valve stenosis (AVS), a progressive disease that leads to
aberrant collagen deposition, leaflet stiffening, and eventual valve calcification at late stages. AVS is also
sexually dimorphic with men having a two-fold higher risk for developing direct calcification, whereas women
with equal disease severity tend to have more valvular fibrosis prior to calcification. The molecular mechanisms
underlying sexual dimorphism in AVS progression remain poorly understood, but growing evidence suggests
AVS is an inflammation-dependent disease. Sex is known to influence the magnitude of the immune response
and function, so we propose to investigate the role of inflammation in sex-specific valve disease progression.
We hypothesize that three major variables contribute to differences in valve calcification in male and female
patients: (1) heightened myofibroblast activation in female valve cells when exposed to inflammatory cues, (2)
elevated expression of bone mineralization inhibitors, such as osteopontin, in female valve cells, and (3) sex-
specific differences in epigenetic machinery. To test these hypotheses, we will develop sex-specific in vitro
models of fibro-calcification that are comparable to diseased valve tissue. We will then investigate the sex-
specific role that macrophage and valvular interstitial cell (VIC) crosstalk has on AVS (Aim 1) and determine the
role of epigenetics in sex-specific regulation of calcification regulators (Aim 2). Ultimately, we aim to identify sex-
specific therapies targeted to VIC populations to slow or halt AVS disease progression (Aim 3).
Istituzione: UNIVERSITY OF COLORADO
PI: KRISTI S. ANSETH, ROBERT M WEISS
Progetto: 5R01HL171197-03
Settori: National Heart Lung and Blood Institute
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