The role of matrifibrocytes in a fibrotic-like response during myxomatous heart valve disease progression - Project Summary Normal heart valve structure and composition are established by valve remodeling, starting at late embryonic stages, and continuing postnatally. Valve remodeling results in a stratified extracellular matrix (ECM), decreased cell density and reduction in cell proliferation. Congenital valve malformations include abnormalities in valve remodeling such as ECM disruption and disorganization. Congenital heart valve abnormalities due to ECM gene mutations and defects, often lead to myxomatous valve disease (MVD). Progressive MVD is characterized by collagen fiber fragmentation, replacement of mucopolysaccharides and proteoglycans, leaflet thickening, and insufficiency, but the mechanisms mediating progressive valve degeneration remain unknown and there are no therapies to prevent or reverse MVD. Recently, our group reported that, in an Fbn1C1041G/+ Marfan syndrome (MFS) mouse model, the ECM mechanics and morphological alterations of the mitral valve occur before functional abnormalities are detectable. Surprisingly, by 6-12 months, collagen fiber remodeling is increased with abnormal fiber organization suggesting a compensatory fibrotic response. We also observed induction of matrifibrocyte gene expression associated with collagen-rich connective tissue such as in myocardial scarring after infarction. In preliminary studies we also observed increased expression of pFAK, a nonconical focal adhesion kinase (FAK), in MVD at the time of increased collagen production and matrifibrocyte gene induction, suggestive of a mechanically regulated myofibroblast response. The role of matrifibrocytes and FAK activation in heart valve disease progression and compensation is unknown. Therefore, we hypothesize that stress activation and collagen overproduction in MFS mitral valves induce matrifibrocytes causing an intrinsic reparative response via activated FAK. We propose three aims to elucidate the role and function of matrifibrocytes in ECM remodeling, maturation and disease. 1: Determine the contributions of fibrotic ECM in MVD progression in mitral valves, 2: Determine if valvular interstitial cell (VICs) activation and matrifibrocyte differentiation occur in response to collagen production and tissue stiffness in mitral valves and 3: To determine if the fibrotic response in the mitral valve during homeostasis and MVD progression is mediated through FAK activation. The K99 portion of this proposal will be carried out in the lab of Dr. Katherine E. Yutzey, an expert in heart valve disease, and co-mentor Dr. Jeffery D. Molkentin, an expert in fibrotic remodeling of the heart. Under their guidance, I will carry out my in vitro (Aims 1-3A) experiments during the K99 phase and start my in vivo (Aims 1-3B) murine model experiments during the K99 phase and continue during the R00 phase. Overall, the comprehensive Aims proposed will provide me with the opportunity to develop an independent research program that will be instrumental in my success as a scientist. Moreover, the data generated will have important implications for cardiovascular science, specifically in development of new therapeutic targets for heart valve disease.
