The bioactive peptide substance P is an important mediator of a wide variety of functions in a wide variety of systems. Althoug substance P belongs to a family of peptides (the tachykinins), it was believed until recently to be the only member of that family in mammals. Implicit in most of the research on substance P was the assumption that no other tachykinins exist in mammals. In 1983, we reported that mammalian tissues contain not only substance P, but also substance K and neuromedin K. We have gone on to show that the three tachykinins have different tissue distributions and different receptors. The discovery of the new tachykinins has cast much of previous substance P research in some doubt, because the great structural similarity of these three peptides probably means that many of the biological functions now thought to be mediated by substance P may in fact be mediated by one of the new peptides. The tools used in substance P research up to now (e.g. the antagonists used in pharmacological studies and the antisera used in immunohistochemical studies) lack the specificity to descriminate between the three mammalian tachykinins. The goal is to further develop and apply techniques for tachykinin research that do have the specificity to discriminate between the various members of the peptide family. Using novel specific antisera for immunocytochemistry (specific aim 1) and novel specific radioligands for receptor studies (specific aim 2), we will be able to confirm (or correct) some current theories about substance P and extent tachykinin research to include all members of the peptide family. Only by the application of such techniques can the vast efforts already invested in substance P research over the last half-century be fully exploited. The significance of the proposed studies is the development of those specific tools and techniques, which will be crucial to research in a wide variety of systems (inflammation, nociception, smooth muscle, etc.) in which tachykinins play an important role.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022961-03
Application #
3405827
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-12-01
Project End
1988-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Mantyh, P W; Ghilardi, J R; Rogers, S et al. (1993) Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J Neurochem 61:1171-4
Maggio, J E; Stimson, E R; Ghilardi, J R et al. (1992) Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci U S A 89:5462-6
Mantyh, P W; Catton, M D; Allen, C J et al. (1992) Receptor binding sites for cholecystokinin, galanin, somatostatin, substance P and vasoactive intestinal polypeptide in sympathetic ganglia. Neuroscience 46:739-54
Mantyh, P W; Catton, M; Maggio, J E et al. (1991) Alterations in receptors for sensory neuropeptides in human inflammatory bowel disease. Adv Exp Med Biol 298:253-83
Too, H P; Maggio, J E (1991) Immunocytochemical localization of neuromedin K (neurokinin B) in rat spinal ganglia and cord. Peptides 12:431-43
Guard, S; Watson, S P; Maggio, J E et al. (1990) Pharmacological analysis of [3H]-senktide binding to NK3 tachykinin receptors in guinea-pig ileum longitudinal muscle-myenteric plexus and cerebral cortex membranes. Br J Pharmacol 99:767-73
Too, H P; Cordova, J L; Maggio, J E (1989) A novel radioimmunoassay for neuromedin K. I. Absence of neuromedin K-like immunoreactivity in guinea pig ileum and urinary bladder. II. Heterogeneity of tachykinins in guinea pig tissues. Regul Pept 26:93-105
Mantyh, P W; Johnson, D J; Boehmer, C G et al. (1989) Substance P receptor binding sites are expressed by glia in vivo after neuronal injury. Proc Natl Acad Sci U S A 86:5193-7
Mantyh, P W; Catton, M D; Boehmer, C G et al. (1989) Receptors for sensory neuropeptides in human inflammatory diseases: implications for the effector role of sensory neurons. Peptides 10:627-45
Mantyh, P W; Gates, T; Mantyh, C R et al. (1989) Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues. J Neurosci 9:258-79

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