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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114611-01
Application #
8351281
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M1))
Program Officer
Evans, Frank
Project Start
2012-08-23
Project End
2017-06-30
Budget Start
2012-08-23
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yutzey, Katherine E; Demer, Linda L; Body, Simon C et al. (2014) Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 34:2387-93
Wallingford, Mary C; Giachelli, Cecilia M (2014) Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm. Mech Dev 133:189-202
Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365-73