The research theme of Dr. Holoshitz' laboratory is the role of signal transduction events in health and disease. Using cellular, molecular, signal transduction and protein chemistry strategies, the laboratory is focusing on three research projects:1. We have recently discovered that the rheumatoid arthritis (RA) shared epitope (SE) is capable of altering important signaling events. The cell surface receptor of the SE has been identified. We are presently characterizing the intracellular events that the SE triggers and deciphering the structure/function requirements of ligand-receptor interaction, using empiric and combinatorial peptide design approaches as well as mutational analysis of the binding domain(s) on the receptor. In a related project, the effect of the SE on endothelial and dendritic cells activation and differentiation is being studied. Beyond their potential utility for understanding immune mechanisms in RA, these studies could provide new insights into MHC-disease association.2. The second project involves non-peptidic phosphoantigens, which activate a subset of T cells, called gamma-delta T cells. We have made progress in understanding the signaling pathway triggered by these compounds. We are currently investigating the effect of phosphoantigens on the cytolytic activity of gamma-delta T cells and the mechanisms involved in attenuation of that activity with SE ligands. 3. The focus of the third project is aberrations in program cell death (apoptosis) signaling in RA. We have identified a pathway that aberrantly attenuates apoptotic signals in lymphocytes and synovial fibroblasts from patients with RA. We are currently focusing on a family of G protein coupled receptors, which transduce the aberrant signal. In addition, proteome and microarray gene expression analyses are being employed to identify gene and protein expression patterns of RA lymphocytes in response to activation of these G protein-coupled receptors.