Inflammation, fibrosis and ectopic calcification are common pathologies observed in calcific aortic valve disease (CAVD). Ectopic calcification is particularly detrimental to the mechanical functions of the vasculature, and is the major cause of valve failure in patients with CAVD, as well as bioprosthetic valves. In CAVD, the major treatment for calcification is valve replacement therapy, which is associated with considerable morbidity and mortality, as well as a significant re- implantation rate. There is currently no drug or cell therapeutics that specifically target prevention and/or regression of calcification in CAVD Our preliminary data suggest that monocyte-derived inflammatory cells have the potential to regulate ectopic calcification in vivo similar to monocyte-derived osteoclasts that regulate and resorb mineral in bone. Our overall hypothesis is that calcifications accumulate in CAVD, in part, due to the absence and/or deficiency of key inflammatory cell functions and mediators, such as those found in osteoclasts that are designed to inhibit and/or regress mineral. By engineering cells to enhance these functions, we may prevent and even remove unwanted calcifications.

Public Health Relevance

Calcific Aortic Valve Disease (CAVD) is due to bone-like mineral deposits in the valve, and is a major cause of heart valve failure and valve replacement. There are currently no drugs that prevent or treat the disease. We propose that part of the reason mineral builds up in the valve is that there are no cells, like bone-resorbing osteoclasts, that can remove the mineral in CAVD. Our studies will use bioengineering approaches to enhance cellular mineral resorption to determine whether this approach might be beneficial in treating CAVD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-N (M1))
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Evans, Frank
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University of Washington
Biomedical Engineering
Schools of Engineering
United States
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Yamada, Shunsuke; Leaf, Elizabeth M; Chia, Jia Jun et al. (2018) PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. Kidney Int 94:716-727
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Wallingford, Mary C; Gammill, Hilary S; Giachelli, Cecilia M (2016) Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and laminin?1 expressing cells. Reprod Biol 16:13-26
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