Vascular calcification (VC), the inappropriate deposition of calcium phosphate salts in cardiac valve and vasculature, is increased with aging, certain genetic disorders, valve disease, coronary artery disease, diabetes and chronic kidney disease. Calcification of these normally compliant organs leads to increased stiffness and/or tendency to rupture, and has severe impacts on hemodynamics and cardiovascular function. Despite the recognized deleterious effects of vascular calcium accrual in blood vessels and valves, there are currently no drug therapies available to directly prevent or treat VC. In the past 20 years, Dr. Giachelli's lab has led studies leading to the paradigm-shifting view that VC is a genetically regulated and cell-mediated process, and thus potentially amenable to treatment. These studies have revealed major genetic pathways, cell types and cellular processes that control the initiation and promotion of VC. Moving forward, the challenge is to understand which of these processes is most important under various disease settings, and key mechanistic pathways and/or deficiencies that might be targeted for therapeutic purposes. Thus, the proposed studies focus on understanding the mechanisms by which 1) vascular and valvular cells undergo osteoblast and chondrocyte-like differentiation, 2) phosphate and phosphate transporters regulate VC, and 3) failed anticalcific mechanisms contribute to VC. The proposed studies are an extension of our previous and current work that aim to identify biomarkers, therapeutic targets and therapies to treat this debilitating process.

Public Health Relevance

Vascular calcification (VC), the inappropriate deposition of calcium phosphate salts in cardiac valve and vasculature, is increased with aging, certain genetic disorders, valve disease, coronary artery disease, diabetes and chronic kidney disease (CKD). Calcification of these normally compliant organs leads to increased stiffness and/or tendency to rupture, and has severe impacts on hemodynamics and cardiovascular function. The studies proposed in this application will provide a foundation for future translational and clinical studies aimed at identifying effective biomarkers and targets, as well as developing therapeutics to prevent and/or treat VC.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL139602-02
Application #
9617281
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
OH, Youngsuk
Project Start
2018-01-01
Project End
2024-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195