PROTEIN KINASE C THERAPEUTIC DEVELOPMENTAL TOOLS

THE LONG-TERM GOALS OF THIS RESEARCH ARE TO CONTRIBUTE TO ANUNDERSTANDING OF THE ROLE OF PROTEIN KINASE C IN NEOPLASTIC TRANSFORMATION AND CELLULAR REGULATION BY SIGNAL TRANSDUCTION PROCESSES. PROTEIN KINASE C FUNCTIONS TO TRANSDUCE SN-1,2-DIACYLGLYCEROL SECOND MESSENGERS, PRODUCED IN RESPONSE TO GROWTH FACTORS, NEUROTRANSMITTERS, HORMONES, AND SOME ONCOGENE PRODUCTS, AND IT IS THE RECEPTOR OF TUMOR PROMOTERS. THE HYPOTHESIS THAT PROTEIN KINASE C MAY BE THE TARGET OF ANTITUMOR AND OTHER THERAPEUTIC AGENTS WILL BE TESTED BY: (1) REFINING MIXED MICELLAR-ASSAY METHODS TO SCREEN FOR PROTEIN KINASE C AGONISTS AND ANTAGONISTS AND THEIR MECHANISM OF ACTION; (2) APPLYING THESE METHODS TO THEPILOT TESTING OF 500 COMPOUNDS, SUBMITTED TO NCI, THAT POSSESS ANTITUMOR ACTIVITY; AND (3) REFINING METHODS OF SN-1,2-DIACYLGLYCEROL QUANTITATION AND APPLYING THEM TO NORMAL AND DISEASED TISSUES. THESE STUDIES ARE DIRECTLY RELATED TO ONCOGENESIS AND ANTITUMOR THERAPEUTIC DEVELOPMENT PROGRAMS. IMPORTANTLY, SUCH ANALYSES WILL ESTABLISH THE DESIRABILITY OF BIOCHEMICALPRESCREENS OF COMPOUNDS SUBMITTED TO THE NCI AND ELUCIDATE CAUSATIVE AGENTS OF CELLULAR TRANSFORMATION. THE CENTRAL INVOLVEMENT OF PROTEIN KINASE C AND SN-1,2-DIACYLGLYCEROL SECOND MESSENGERS IS RELEVANT TO ENDOCRINOLOGY, NEUROLOGY, GROWTH, DIFFERENTIATION, DEVELOPMENT, ARTHRITIS AND OTHER INFLAMMATORY RESPONSES, SMOOTH MUSCLE CONTRACTION, PSORIASIS, DIABETES, AND OTHER HUMAN CONDITIONS.