Uremic vascular calcification (UVC) is not simply a result of elevated phosphorus and calcium levels. Disregulation in inhibitory and promoting factors, greatly contribute to mineralization in vessels. Osteogenic differentiation in VSMC has emerged as a potential pathogenetic mechanism for UVC during last decade. Runx2 is the master gene for osteogenic program and without it VSMC cannot undergo osteochondrogenesis. Based on our preliminary results, we hypothesize, that, osteogenic differentiation may promote, but is not an absolute requirement for vascular calcification. Unfortunately, to test this hypothesis, embryonic Runx2 KO, or isoform selective Runx2-I or Runx2-II KO mice cannot be used. These mice do not survive long enough to be used in prolonged uremic experiments. We propose to use aorta transplantation from mice with Runx 2 gene isoform specific, as well as total Runx2 inactivation into WT mice to create VSMC specific Runx2 KO chimeras and test the effect of complete inhibition of VSMC osteogenic differentiation on vascular calcification in uremia. We also propose to examine if Runx2 overexpression is capable of launching osteogenic program in vessels in otherwise normal mice, mice fed high phosphorus diet and in uremic mice. Inducible global Runx 2 overexpression mouse model exists, but mice only survive 2 weeks, not long enough to develop vascular calcification. We will use the aorta transplantation technique to create chimeras with VSMC-specific Runx2 overexpression to test its effects on vascular osteogenesis and calcification.

Public Health Relevance

Runx2 mediated osteogenic differentiation in VSMC may have pathogenic role in vascular calcification in uremia. We hypothesize, that vascular calcification may occur without osteogenic differentiation. Runx 2 deficiency aborts osteogenic program in all cells including bones. We propose to use Runx 2 deficient and overexpression mice models in uremic vascular calcification experiments, in order to elucidate role of osteogenesis in vascular calcification.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK097457-02
Application #
8634775
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$78,000
Indirect Cost
$28,000
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322