Decreased signaling through the T cell receptor at the thymic level causes rheumatoid arthritis in the SKG mouse -which carries a mutation of ZAP-70 able to impair the activation of the kinase- as well as in human patients carrying sporadic mutations of ZAP-70. We reported that the low molecular weight protein tyrosine phosphatase (LMPTP) is a positive regulator of T cell receptor signaling. In T cells LMPTP is able to dephosphorylate the tyrosine kinase ZAP-70 on the negative regulatory Tyr-292, and increase ZAP-70 activation after TCR engagement. In this proposal we will test the hypothesis that increased expression of LMPTP at the thymic level under control of the LCK proximal promoter is able to rescue the arthritis phenotype of SKG mice. As a result of our experiments we expect to confirm the relevance of LMPTP as a modulator of ZAP-70 and T cell receptor signaling, and validate the LMPTP as a candidate gene/genetic modifier in rheumatoid arthritis. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR054053-03
Application #
7485089
Study Section
Special Emphasis Panel (ZAR1-EHB-J (M1))
Program Officer
Mancini, Marie
Project Start
2006-09-20
Project End
2009-09-30
Budget Start
2008-09-01
Budget End
2009-09-30
Support Year
3
Fiscal Year
2008
Total Cost
$9,470
Indirect Cost
Name
University of Southern California
Department
Orthopedics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089