The clinical condition of gingival overgrowth consists of excess gingival tissues that creates disturbances in the oral environment and creates related systemic complications. Drug-induced gingival overgrowth occurs as a side effect of certain medications. Previous studies from our laboratory have shown that phenytoin induced gingival overgrowth lesions are more fibrotic, less cellular, and contain elevated levels of connective tissue growth factor (CTGF) than lesions formed from the pharmacological action of cyclosporine-A or nifedine. This finding is significant since CTGF is capable of stimulating the accumulation of insoluble collagen in cultured human gingival fibroblasts. Additionally, CTGF levels are elevated in other fibrotic conditions including, but not limited to, scleroderma, atherosclerosis, and kidney failure. The regulation and downstream consequences of increased CTGF expression currently are not well understood. Preliminary data indicate that prostaglandin E2 (PGE2) is capable of up-regulating CTFG expression in gingival fibroblasts and this effect is tissue-specific. The goals of the current proposal are (1) to determine the intracellular pathways through which PGE2 regulates CTGF expression in primary human gingival fibroblasts, (2) compare this response with other tissue-derived fibroblasts including human primary dermal fibroblasts, primary human renal mesangial cells, and control human fetal lung (IMR9O) fibroblasts, (3) determine the molecular mechanism underlying overgrowth and scleroderma by comparison with normal gingival and dermal fibroblasts, and (4) determine the target genes regulated by CTGF, specifically those involved with the normally tightly coupled processes of extracellular matrix degradation and biosynthesis. We hypothesize that tissue-specific differences exist in the regulation of CTGF expression. By defining the tissue-specific pathways by which PGE2 regulates CTGF expression we will provide a foundation by which therapeutic strategies targeted against specific fibrotic pathologies may be formulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DE016609-04
Application #
7457828
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Hardwick, Kevin S
Project Start
2005-09-07
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$128,493
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118