This proposal for a Physician scientist Award outlines a training program designed to provide the P.I. with a broad based educational experience upon which to establish a career as an independent investigator. The program plan consists of formal coursework in Microbiology along with a research project which is designed to provide the P.I. with intensive training in bench research. The research focus of this project centers on a comparative analysis of four pathways of human T lymphocyte activation. It is known that T lymphocytes can be activated using monoclonal antibodies against the CD2, CD3, CD28, and CD69 pathways. Relatively little work has been done comparing these pathways, but it appears that differences do exist between them. Lymphocyte activation through these pathways will be studied, including a comparative analysis of cytokine mRNA production by PCR, proliferative response by thymidine incorporation, protein tyrosine kinase phosphorylation in cellular substrates by immunoblotting, and proto-oncogene mRNA production determined by Northern analysis. Unique phosphotyrosine proteins will be further characterized. Subsets of T lymphocytes such as CD4+, CD8+, CD45RA+, and CD45RO+ will be examined in order to determine differences in these subsets. This information will then serve as a baseline to study lymphocyte activation in systemic rheumatic disease. Systemic lupus erythematosus and rheumatoid arthritis will serve as models as both of these disorders have been implicated as having abnormalities of T lymphocyte function. It is the purpose of this study to serve as a training vehicle to allow the P.I. to develop into an independent investigator. It is hoped that these studies will lead to a better understanding of normal T cell activation along with potentially leading to further insight into the mechanisms of rheumatic disease. Additionally, this work should serve as a foundation leading to further research by the P.I. in rheumatic disease.
| Haire, R N; Ohta, Y; Lewis, J E et al. (1994) TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12. Hum Mol Genet 3:897-901 |
