Cadherin-11 in calcific aortic valve disease

PROJECT SUMMARY/ABSTRACT Age-related heart valve disease is the 3rd leading cause of cardiovascular disease and is especially prevalent among the elderly. Studies have shown that degenerative aortic valve disease affects over 25% of people over 65 years of age, and eventually leads to calcific aortic valve disease (CAVD). There is no effective medical therapy that modifies the progression of CAVD. CAVD is believed to be primarily driven by the valve interstitial cells (VICs). Briefly, when these normally quiescent VICs become ‘activated’ via unknown mechanisms, they become myofibroblasts and express smooth muscle α–actin and cadherin-11 (CDH11). We have generated robust evidence over the past decade to advance CDH11 as a prime candidate for CAVD therapy. Our hypothesis is that CDH11 is the mechanobiological driver of the majority of cases of CAVD and that targeting it can halt the progression and possibly reverse CAVD. Therefore, we propose three aims to advance targeting of CDH11 for treatment of CAVD. Aim 1: Clarify the cell-cell-specific mechanism of CDH11 engagement that leads to CAVD. Aim 2: Determine if targeting CDH11 can halt or reverse AS progression. Aim 3: Evaluate circulating CDH11 as a biomarker to identify interventional timing in AS patients. At the conclusion of these aims, we will have clarified the precise cell-cell interaction by which CDH11 drives CAVD, established if targeting CDH11 after the development of CAVD can halt or reverse the pathology, and determined if circulating CDH11 can be used as a biomarker in the progression of AS to guide a future clinical trial.