HUMAN CDNA/GENE FOR AN IMMUNOSUPPRESSANT-BINDING PROTEIN

THIS PHASE I PROJECT WILL CONDUCT EXPERIMENTS TO INITIATE MOLECULAR ANALYSIS OF THE HUMAN CDNA AND GENE ENCODING FK-506 BINDING PROTEIN (FK-506 BP), A CYTOSOLIC PROTEIN THATBINDS THE POTENT IMMUNOSUPPRESSOR FK-506. FK-506 IS A RECENTLY DISCOVERED IMMUNOSUPPRESSIVE COMPOUND THAT IS SIGNIFICANTLY MORE POTENT THAN CYCLOSPORIN A, A WIDELY USED IMMUNOSUPPRESSANT OF ENORMOUS COMMERCIAL VALUE. IMMUNOSUPPRESSANTS ARE COMPOUNDS THAT REDUCE THE IMMUNE RESPONSE; THEY ARE CRUCIAL TO TRANSPLANTATION SURGERY, PREVENTION OF GRAFT REJECTION, AND CONTROL OF AUTOIMMUNE DISEASES. THEY COMPRISE A BURGEONING COMMERCIAL MARKET. THIS WORK WILL PROVIDE A FOUNDATION FOR RESEARCH FOCUSED ON DEFINING THE INTERACTION BETWEEN FK-506 BP AND FK-506 AT THEATOMIC LEVEL AND ON UNDERSTANDING THE IMMUNOMODULATORY PROPERTIES OF FK-506. SUCH KNOWLEDGE WILL FACILITATE EFFORTS TO DESIGN AND DEVELOP NEW IMMUNOSUPPRESSANTS WITH HIGHER POTENCY AND LOWER TOXICITY THAN CYCLOSPORIN A. THE SPECIFIC AIMS ARE TO: (1) ISOLATE A FULL-LENGTH HUMAN FK-506 BP CDNA, (2) DETERMINE THE COMPLETE NUCLEOTIDE SEQUENCE OF THIS CDNA CLONE, (3) UTILIZE THE CLONED CDNA TO ISOLATE THE HUMAN FK-506 GENE, (4) CHARACTERIZE THE GENOMIC CLONE RELATIVE TO THE CDNA CLONE, AND (5) DETERMINE WHETHER THERE ARE FK-506 BP-RELATED GENES IN THE HUMAN GENOME. THESE AIMS WILL BE ACCOMPLISHED USING KNOWLEDGE OF THE AMINOTERMINAL SEQUENCE OF FK-506 BP AND STANDARD MOLECULAR BIOLOGICAL TECHNIQUES.