The principal investigator's training and research interests relate to the functions and regulation of the gastrointestinal endocrine system. The applicant is completing fellowship training in gastroenterology and is committed to a career of laboratory investigation in academic gastroenterology. The long term goal of this proposal is to elucidate the biological role of secretin, a gastrointestinal hormone which regulates pancreatic secretion. More specifically, the aims of this proposal are to define the secretin precursor protein, to determine the tissue distribution of secretin gene expression, and to determine how secretin gene expression is regulated. To accomplish these aims, full length cDNA's encoding porcine and rat secretin will be cloned. From the nucleotide sequence of the cDNA's encoding porcine and rat secretin will be cloned. From the nucleotide sequence of the cDNAs, the amino acid sequence of the secretin precursor will be deduced. From the sequence of the precursor peptide, it will be possible to predict all of the potential peptides that can be generated by post-translational cleavage. Probes generated from the cDNA, will be used to establish the tissues in which the secretin gene is expressed. In particular, these studies will address whether secretin is produced in brain. By generating a map of the secretin producing cells in the CNS using in situ hybridization, the function of secretin in the brain may be clarified. Secretin producing cells will be characterized further by combining in situ hybridization with immunocytochemistry to see if other peptides are coexpressed with secretin. The cDNA probes will be used to study the regulation of secretin mRNA levels by different signal transduction pathways in a secretin producing cell line. Finally, the role of established secretin secretagogues in regulation of secretin mRNA levels will be studied in vivo in rats. These studies will be carried out in the of the Division of Gastroenterology in space adjacent to Dr. Letter's lab. The Division of Molecular Medicine is located one floor below. The expertise available in both the sponsor's and cosponsor's laboratories includes extensive experience in the molecular biology of gastrointestinal peptide hormones as well as familiarity with all the methodology proposed in this application. This will provide an ideal environment to facilitate the applicant's transition to independent investigator.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes and Digestive and Kidney Diseases Special Grants Review Committee (DDK)
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Tufts University
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Kopin, A S; Beinborn, M; Lee, Y M et al. (1994) The CCK-B/gastrin receptor. Identification of amino acids that determine nonpeptide antagonist affinity. Ann N Y Acad Sci 713:67-78
Lee, Y M; Beinborn, M; McBride, E W et al. (1993) The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization. J Biol Chem 268:8164-9
Kopin, A S; Lee, Y M; McBride, E W et al. (1992) Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A 89:3605-9
Kopin, A S; Wheeler, M B; Nishitani, J et al. (1991) The secretin gene: evolutionary history, alternative splicing, and developmental regulation. Proc Natl Acad Sci U S A 88:5335-9
Kopin, A S; Wheeler, M B; Leiter, A B (1990) Secretin: structure of the precursor and tissue distribution of the mRNA. Proc Natl Acad Sci U S A 87:2299-303