Overview

This program has two major components. One relates to the molecular basis of gastrointestinal hormone action, with focus on the structure, function, and regulation of receptors, and particular interest in the roles of these regulatory molecules in the development and progression of pancreatic and colon cancer and in dysmotility states. There has been major emphasis on cholecystokinin (CCK)-gastrin, secretin-vasoactive intestinal polypeptide (VIP), and motilin families of peptides and receptors. Work on the molecular basis of hormone binding to receptors has included molecular biological and novel chemical approaches. This is directed toward gaining insight into the conformations of ligands and their receptors, as well as the way these pairs of molecules interact. A clear understanding of these structures provides a basis for the rational design of new drugs that might selectively activate or block cellular signaling pathways. These studies utilize the synthesis of series of analogues of the peptide hormones, mutagenesis of the receptors, and the design, synthesis and application of photolabile probes for the affinity labeling of receptor domains. All of this is directed toward the acquisition of constraints that can be utilized to refine three-dimensional molecular models. Much attention is also focused on the dynamic changes in conformation of the ligand-receptor complex that results in initiation of signaling pathways within the cell. These are probed utilizing novel fluorescence methodologies.

Receptor signaling is regulated by biochemical and cellular mechanisms that differ in distinct types of cells and in tumors versus healthy cells. Characterization of these processes is another interest of the laboratory, providing still another site for potential therapeutic intervention in disease. Hormones and receptors have also been shown to be capable of influencing the growth of normal cells and the progression and invasiveness of some tumors. This laboratory has been quite interested in the investigation of hormone-receptor systems in each phase of tumor development, and in the behavior of tumors and their response to specific therapeutic strategies. Abnormalities in the splicing of CCK and secretin receptors demonstrated to exist in pancreatic cancer by this laboratory may contribute to the aggressive behavior and poor prognosis of this tumor.

A second major area of interest relates to mRNA splicing and alternative splicing as a manifestation of disease. While alternative splicing of receptors of interest that occurs in cancer represented the major introduction to this field, extensive missplicing as a manifestation of cancer has resulted in substantial activity directed more broadly to this process. There are activities to discover the missplicing events in various diseases, to utilize this information in diagnostics and therapeutic approaches, as well as to better understand the mechanisms responsible for missplicing.