Thursday, April 3, 2025
4/3/2025
Effects of early Retinoic Acid signaling on valve development - Project Summary/Abstract Congenital valve defects (CVDs) constitute some of the most common human congenital heart defects (CHDs). CVDs that lead to valve disease later in life, which can result in heart failure, stroke, blood clots, and even sudden cardiac arrest. The most common therapy for valve diseases is invasive valve replacement surgery, which is one of the most common procedures in the cardiac surgery market at nearly 182,000 per year in the USA, making up nearly a quarter of the total procedural volume. Therefore, elucidating the early developmental and patterning mechanisms driving normal cardiac valve development will give us novel insight into the etiology of CVDs. Retinoic acid (RA) is the most active metabolic product of Vitamin A (retinol) within vertebrate embryos and is reiteratively required for normal vertebrate heart development. Perturbations of RA signaling have been associated with multiple types of CHDs, including CVDs, as well as valve diseases at later stages of development. However, embryos devoid of early RA exhibit enlarged hearts due to the increased specification and differentiation of cardiomyocytes. Despite the known requirements in heart development and previous studies implying RA signaling is required for cardiac valve formation and maintenance, we still do not have clear understanding of the requirements of early RA signaling in vertebrate valve development. Our preliminary work using zebrafish shows that early inhibition of RA signaling results in an enlarged atrioventricular canal (AVC), characterized by an expansion of myocardial AVC markers, which is consistent with the enlarged hearts in RA deficient embryos. Surprisingly, despite the enlargement of the myocardial AVC region in RA deficient embryos and expectation that this would result in typically larger valves, we find that the overlying atrioventricular valves (AVVs) do not form, suggesting that a factor signaling from the myocardium to the overlying endocardium necessary to promote AVV induction is lost. Our preliminary data show that canonical Wnt signaling is lost within AVC cardiomyocytes following early inhibition of RA, suggesting that we have identified a new signaling node necessary to promote normal AVV development. In Aim 1, we will test the hypothesis that early RA signaling directly establishes cardiac progenitors sufficient to turn on Wnt signaling later in the AVC myocardium required for AVV development. In Aim 2, we will test the hypothesis that Wnt signaling functions downstream of early RA signaling in the induction of AVVs. Ultimately, the proposed studies could be used to identify and develop new therapeutic approaches for treatment to prevent or ameliorate CVDs and their resulting valve diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).