Rheumatoid Arthritis (RA) is an autoimmune disease that affects people world wide. The underlying mechanism is unknown, but patients tend to have high levels of tumor necrosis alpha (TNF) in their joints. TNF helps protect the body when under stress, but it can also be damaging to un-infected cells and the surrounding tissue by causing inflammation leading to production of harmful proteins and destruction of non-inflammed areas. Despite advances in medicine, anti-inflammatory therapies currently available are not totally effective and are often costly, thus, novel therapies are needed. Sphingolipids are found in the cell membrane but have also been shown to be involved in the cellular pathways that promote inflammation. One specific sphingolipid, sphingosine-1-phosphate (S1P), has been shown in the literature to cause an increase in inflammatory mediators. Addition of S1P leads to increased prostaglandin E2 (PGE2) and COX-2 protein. Simultaneous stimulation with TNF and S1P increases PGE2 and COX-2 more than S1P alone. Therefore, decreased formation of S1P has been hypothesized to lead to decreases in inflammation. S1P is formed through the action of sphingosine kinase (SphK) 1 and 2;however SphK1 is the major enzyme responsible for S1P formation in the inflammatory pathway. Using siRNA to remove of SphK1 in fibroblast cells lead to decreases in S1P, COX-2, and PGE2 formation. The effects seen after TNF stimulation in these cells were removed with the elimination of SphK1 suggesting a relationship between TNF and SphK1. The goal of this project is to study the effects of SphK1 on inflammation in mice that over express human TNF, like RA patients, and do not have a working copy of the SphK1. In preliminary investigations, mice that are missing functional copies of SphK1 have decreased arthritis score despite the fact that TNF alpha is being expressed at constant levels.
The aims of the study are 1) determine the contribution of sphingosine kinase 1 in the pathogenesis of TNF alpha induced arthritis in vivo;2) characterize gene expression in joints from TNF alpha transgenic mice with and without functioning copies of SphK1;3) determine the mechanism in which removal of SphK1 affects inflammation using FLS. The primary methodology of these studies will be to utilize the TNF/SphK1 mouse model to determine the mechanism of SphK1 affects inflammation. Relevance: This project seeks to define the significance of TNF alpha and SphK1 in chronic inflammation, potentially leading to the discovery of a novel therapeutic target for chronic inflammatory diseases like RA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AR057307-02
Application #
7918940
Study Section
Special Emphasis Panel (ZRG1-DIG-E (29))
Program Officer
Mao, Su-Yau
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$38,331
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
Baker, DeAnna A; Obeid, Lina M; Gilkeson, Gary S (2011) Impact of sphingosine kinase on inflammatory pathways in fibroblast-like synoviocytes. Inflamm Allergy Drug Targets 10:464-71
Baker, DeAnna A; Barth, Jeremy; Chang, Raymond et al. (2010) Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-induced arthritis. J Immunol 185:2570-9