Cardiac valvular calcification is the predominant pathology necessitating cardiac valve replacement. However, the molecular mechanisms that result in cuspal calcification are unknown. Prior theories of valve calcification have emphasized a degenerative process involving mineralization of valves. Recent findings, however, suggest that valve calcification is not passive degeneration, but an active ongoing process that involves not only mineralization, but ossification or formation of bone. Bone extracellular matrix proteins have been identified in calcified valves and are thought to provide the framework for the calcification process. Furthermore, inflammatory cells such as macrophages and lymphocytes have been identified in calcified cardiac valves. The hypothesis of this proposed research is that cardiac valve calcification occurs due to a change in the cellular phenotype of an osteoblast-like progenitor cell in cardiac valves. These osteoblast- like cells secrete proteins such as bone extracellular matrix proteins, alkaline phosphatase and Collagen resulting in ossification and mineralization of the valve. Bone forming proteins, inflammatory cells and growth factors are necessary pathologic components for the calcification process.
The aims of this study are: 1. To compare the phenotypic characteristics of cells and proteins associated with ossified and mineralized portions of calcified cardiac valves. 2. To investigate mechanisms of valve calcification using a cell culture model of calcification. 3. To examine therapeutic strategies to inhibit valve calcification with a bisphosphonate in cell culture.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003974-03
Application #
6351440
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Program Officer
Commarato, Michael
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$130,923
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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