Wednesday, April 2, 2025
4/2/2025
Mechanosensitive Mechanisms of Premature Calcification in Bicuspid Aortic Valve Disease - PROJECT SUMMARY Bicuspid aortic valve (BAV) disease is the most prevalent congenital heart disease, affecting ~2% of the population worldwide. This disorder is characterized by the formation of two, rather than three valve cusps, leading to narrowing of the valve opening and increased mechanical stress. The structural defect is not what requires clinical intervention, but rather the development of premature calcific aortic stenosis (CAS) in ~50% of BAV patients. The association between BAV-induced mechanical stress and premature CAS is poorly understood, resulting in medical treatment options that for severe CAS, is currently limited to surgical aortic valve (AoV) replacement with associated complication. Therefore, there is a critical need to mechanistically determine if, and how BAV-induced mechanical stress promotes early onset calcification at molecular and cellular levels. The pathobiology of BAV-related premature calcification in young adults is poorly understood, although collective reports suggest that abnormal mechanical stress induced by the structural malformation of the AoVs play a role; however, this has not been directly investigated. Therefore, a major goal of my research is to address this using mouse models of human disease integrated with innovative in vitro assays and molecular biology techniques to enhance my training. The foundation for this work was initiated by previous studies in the lab that performed computational modeling in parallel with spatial transcriptomics to correlate regions of high mechanical stress with activation of a calcification gene expression program. My more recent preliminary data further shows that these regions also associate with enrichment of differentially expressed genes that associate with ‘ATP- metabolic processes’, including increased expression of ATP purinoreceptor, p2rx4, that I have shown to be required for expression of calcification genes in valve interstitial cells. Based on these data and additional preliminary studies, I hypothesize that BAV-induced mechanical stress leads to VEC-mediated ATP release, that acts upon p2rx4 in VICs, initiating pre-calcific molecular changes. To test this, I will perform two specific aims: Aim 1. Delineate the BAV-specific mechanosensitive signaling pathway between VECs and VICs that promotes early onset calcification. Aim 2. Determine if p2rx4 antagonism can prevent and treat premature calcification in mouse models of BAV. Outcomes from these studies will provide substantial insight on the relationship between biomechanical stress and molecular changes in the valve, while also identifying a potential target for therapeutic drug development, to prevent the onset of CAS in BAV patients.
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