The long-term objective of this project is elucidation of the molecular mechanisms responsible for microvascular injury and upregulated deposition of the extracellular matrix (ECM) in systemic sclerosis (SSc). Recent studies from our laboratory strongly suggest that a member of the Etsl family of transcription factors, Flil, may contribute to the uncontrolled ECM deposition in SSc lesions. Our recent data also demonstrate that Flil is prominently expressed in endothelial cells in healthy skin and is downregulated in endothelial cells in SSc lesions obtained from clinically uninvolved skin. The specific role of Flil in normal adult vessels is currently unknown. However, the phenotype of Flil knockout strongly suggests that Flil is involved in vascular remodeling and survival of endothelial cells during embryonic development. We hypothesize that downregulation of Flil is a critical pathogenic event that leads to endothelial cell dysfunction and ultimately death, simultaneous with dysregulated collagen production by fibroblasts. We propose two specific aims to test this hypothesis.
In Aim 1 we will examine the regulation and function of Flil using human dermal microvascular endothelial cells (HDMECs).
In Aim 2 we will employ a three-dimensional organotypic coculture of HDMECs and dermal fibroblasts to determine the role of Flil in capillary network formation. Once optimized, this experimental model will allow us to reproduce more closely the physiologic and pathologic conditions existing in healthy and SSc skin. These studies may help us to unravel the molecular basis of the disease and ultimately provide the logical target for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR050798-01
Application #
6733999
Study Section
Special Emphasis Panel (ZAR1-TAS-D (O2))
Program Officer
Gretz, Elizabeth
Project Start
2003-09-30
Project End
2005-05-31
Budget Start
2003-09-30
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$146,000
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Chintalapudi, Mastan R; Markiewicz, Margaret; Kose, Nurgun et al. (2008) Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells. Carcinogenesis 29:696-703