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 #
5R01HL114611-03
Application #
8697123
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Evans, Frank
Project Start
2012-08-23
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Jackson, Melissa F; Scatena, Marta; Giachelli, Cecilia M (2017) Osteoclast precursors do not express CD68: results from CD68 promoter-driven RANK transgenic mice. FEBS Lett 591:728-736
Wallingford, Mary Catherine; Chia, Jia Jun; Leaf, Elizabeth M et al. (2017) SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification. Brain Pathol 27:64-76
Yamada, Shunsuke; Giachelli, Cecilia M (2017) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 100:87-93
Giachelli, Cecilia M; Speer, Mei Y (2017) Noncanonical Wnts at the Cusp of Fibrocalcific Signaling Processes in Human Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 37:387-388
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-1036
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
Eaton, K V; Yang, H L; Giachelli, C M et al. (2015) Engineering macrophages to control the inflammatory response and angiogenesis. Exp Cell Res 339:300-9
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
Paloian, Neil J; Giachelli, Cecilia M (2014) A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol 307:F891-900
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

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