The long term goal of this research program is to expand the basic knowledge of biological information transfer from nerve cell to target cell by peptides. This particular research focuses on the final stages of neuroendocrine processes where the information is transferred from the peptide messenger to the target cell receptor. We will concentrate on both the molecular properties of the hormone and the structure of the receptor. The model for our research is the insect hypertrehalosemic neurohormone (HTH, pGlu-Val-Asn-Phe-Ser-Pro-Gly-Trp-Gly-Thr-NH2). The hormone was isolated from nerve tissue of the tropical cockroach Blaberus discoidalis by our laboratory. The major observed function of this peptide in B. discoidalis is elevation of blood sugar concentration, an action similar to that of glucagon in vertebrates. The unique and extensive knowledge of this laboratory for HTH structure-activity relationships will be the basis for the research approach. The research at Texas A & M will continue to use this non- controversial laboratory organism (B. discoidalis) to expand knowledge about neuroendocrine systems and peptide-receptor interactions. This laboratory is working closely with organic chemists whose major goal is the development of peptide beta-turn mimetics for potential pharmaceuticals for the treatment of AIDS and Alzheimer's disease. HTH is a good model to test the beta-turn mimetics developed by our collaborators because our structure- activity studies suggest that a beta-turn in HTH orients other critical residues for receptor interaction. Simple, economical assays are available to test the results of mimetic inclusion . The information that we glean from this model system can provide assistance for the design of future pharmaceuticals and the development of rational plans for insect control leading to a reduction of vector-borne diseases. The specific objectives of the proposed research are to use peptide synthesis and peptide analysis in conjunction with our assay systems to: 1. Develop radioHTH-receptor binding assays to characterize receptor tissue distribution, occupancy and kinetic parameters; 2. Develop radioHTH photoaffinity probes to confirm receptor tissue distribution and gain molecular information on receptor molecules; 3. Continue analog studies to determine the properties of HTH required for binding and signal transduction, and attempt to develop receptor antagonists through the use of restricted conformational analogs and mimetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020137-08
Application #
3400328
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1984-09-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Type
Schools of Earth Sciences/Natur
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Hayes, T K; Strey, A; Belk, S et al. (1997) Biochemical characterization of mosquito kinin and related receptors. Ann N Y Acad Sci 814:342-5
Gade, G; Hayes, T K (1995) Structure-activity relationships for Periplaneta americana hypertrehalosemic hormone. I: The importance of side chains and termini. Peptides 16:1173-80
Hayes, T K; Guan, X C; Johnson, V et al. (1994) Structure-activity studies of allatostatin 4 on the inhibition of juvenile hormone biosynthesis by corpora allata: the importance of individual side chains and stereochemistry. Peptides 15:1165-71
Strey, A; Hayes, T K; Isaac, R E (1993) Metabolism of insect hypertrehalosemic hormone in Blaberus discoidalis cockroaches. Biochem Soc Trans 21 ( Pt 3):244S
Schoofs, L; Holman, G M; Hayes, T K et al. (1991) Isolation, primary structure, and synthesis of locustapyrokinin: a myotropic peptide of Locusta migratoria. Gen Comp Endocrinol 81:97-104
Schoofs, L; Holman, G M; Hayes, T K et al. (1990) Isolation, identification and synthesis of locustamyotropin (Lom-MT), a novel biologically active insect peptide. Peptides 11:427-33
Hayes, T K; Keeley, L L (1990) Structure-activity relationships on hyperglycemia by representatives of the adipokinetic/hyperglycemic hormone family in Blaberus discoidalis cockroaches. J Comp Physiol B 160:187-94
Hayes, T K; Pannabecker, T L; Hinckley, D J et al. (1989) Leucokinins, a new family of ion transport stimulators and inhibitors in insect Malpighian tubules. Life Sci 44:1259-66
Keeley, L L; Sowa, S M; Hayes, T K et al. (1988) Neuroendocrine and juvenile hormone effects on fat body protein synthesis during the reproductive cycle in female Blaberus discoidalis cockroaches. Gen Comp Endocrinol 72:364-73
Hayes, T K; Keeley, L L; Knight, D W (1986) Insect hypertrehalosemic hormone: isolation and primary structure from Blaberus discoidalis cockroaches. Biochem Biophys Res Commun 140:674-8