This Phase I proposal describes experiments to initiate molecular analysis of the human cDNA and gene encoding FK-506 Binding Protein (FK-506 BP), a cytosolic protein that binds 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. The work proposed here will provide a foundation for research focused on defining the interaction between FK-506 BP and FK-506 at the atomic level and on understanding the immunomodulatory properties of FK-506. Such knowledge, in turn, will facilitate efforts to design and develop new immunosuppressants with higher potency and lower toxicity than cyclosporin A.
The specific aims of this proposal 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 amino terminal sequence of FK-506 BP and standard molecular biological techniques.
