POTENTIAL COSTIMULATORY MOLECULE

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DESCRIPTION (adapted from applicant's abstract): Identification and characterization of a novel costimulatory molecule may be important in the determination of the primary changes in mechanisms that lead to the age-related loss of immune function. The members of the tumor necrosis factor receptor (TNFR) superfamily are involved in the cell death, survival and differentiation. We have identified a new member of the TNFR superfamily named TR2. TR2 possesses the extracellular cysteine-rich motif that is characteristic to the TNFR family, and showed similarities to TNFR-II, CD40 and 41BB. Its mRNA detected preferentially in Lymphoid cells and was inducible. Blocking the interaction between TR2 and its ligand inhibited mixed-lymphocyte-reaction (MLR). We hypothesize that TR2 interacts with a new member of TNF ligand superfamily and displays a costimulatory function in lymphocyte activation. To understand its bioactivities and to test the hypothesis, we propose three specific aims; 1 ) to identify TR2 ligand and to determine the molecular characteristics of the ligand; 2) to determine the biological functions of TR2; and 3) to identify signaling molecules associated with the cytoplasmic tail of the receptors and characterize the molecules. We believe that the determination of the function of TR2 will enhance our understanding and biological significance of TNF and TNFR superfamily, and enhance our capability to apply these important molecules for the treatment of human autoimmune diseases and age-related immune dysfunctions.