This is a revised application for competitive renewal of K02 support for Dr. John W. Haycock. This award will enable Dr. Haycock to continue his scientific development and to pursue his recently funded research program (MH55208) on brain monoaminergic systems in mental illnesses, which was initiated and developed over the course of the current award. The ability to study clinical issues related to catecholamine function concurrently with his previously established fundamental neuroscience research program (NS25134) has realized one of the candidate's major long-term goals. As a result, the candidate's short-term goals are focused upon development of his laboratory by recruiting younger scientists to participate in effecting the scientific goals of both the clinical and fundamental research projects. In addition to developing his role as a laboratory director, the candidate will continue his scientific development by pursuing a novel, multidisciplinary approach which he has recently developed, using antibodies to labile epitopes for studying the regulation of signaling molecules in vivo. The proposed research plan focuses upon tyrosine hydroxylase (TyrOH) and tryptophan hydroxylase (TrpOH), which catalyze the initial and rate- limiting steps in catecholamine (dopamine and norepinephrine) and serotonin biosynthesis, respectively. Alterations in each of these systems have been implicated in mental disorders and, in particular, schizophrenia. TyrOH is highly regulated--by protein phosphorylation in the short-term and by transcriptional control in the long-term; and, alternative splicing (which occurs exclusively in monkeys and humans) produces multiple TyrOH isoforms and perhaps, an additional level of regulation. By contrast, comparatively little is known about TrpOH, despite its evolutionary and functional proximity to TyrOH. Postmortem human brain tissue will be analyzed using quantitative blot immunolabeling techniques and a bank of antibodies developed for this purpose by the applicant. TyrOH and TrpOH protein levels, as well as the relative abundances of TyrOH isoforms, will be measured in neurochemically appropriate brain regions dissected from cryostatic sections. DOPA decarboxylase (immediately downstream of both TyrOH and TrpOH) and dopamine beta-hydroxylase (which converts dopamine to norepinephrine) protein levels will also be quantitated, and similar assays have been developed for another class of presynaptic monoaminergic markers--the vesicular and plasmalemmal monoamine transporters. The primary study groups will consist of (a.) suicide/sudden death victims having confirmed diagnoses of schizophrenia and (b.) age-matched, sudden-death control subjects having no Axis 1 mental disorder. Parallel, collaborative studies of major depressives will provide comparison groups and allow identification of potential disease-specific differences.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research (K02)
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Special Emphasis Panel (ZRG1-MDCN-5 (01))
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Meinecke, Douglas L
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
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Salvatore, Michael F; Zhang, Jin-Lu; Large, Delia M et al. (2004) Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. J Neurochem 90:245-54
Hui, Anna S; Striet, Justin B; Gudelsky, Gary et al. (2003) Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons. Hypertension 42:1130-6
Haycock, John W; Becker, Laurence; Ang, Lee et al. (2003) Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J Neurochem 87:574-85
Haycock, John W (2002) Species differences in the expression of multiple tyrosine hydroxylase protein isoforms. J Neurochem 81:947-53
Lindgren, Niklas; Goiny, Michel; Herrera-Marschitz, Mario et al. (2002) Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain. Eur J Neurosci 15:769-73
Haycock, John W; Kumer, Sean C; Lewis, David A et al. (2002) A monoclonal antibody to tryptophan hydroxylase: applications and identification of the epitope. J Neurosci Methods 114:205-12
Haycock, John W (2002) Peptide substrates for ERK1/2: structure-function studies of serine 31 in tyrosine hydroxylase. J Neurosci Methods 116:29-34
Waymire, Jack C; Haycock, John W (2002) Lack of regulation of aromatic L-amino acid decarboxylase in intact bovine chromaffin cells. J Neurochem 81:589-93
Salvatore, M F; Waymire, J C; Haycock, J W (2001) Depolarization-stimulated catecholamine biosynthesis: involvement of protein kinases and tyrosine hydroxylase phosphorylation sites in situ. J Neurochem 79:349-60
Kish, S J; Kalasinsky, K S; Derkach, P et al. (2001) Striatal dopaminergic and serotonergic markers in human heroin users. Neuropsychopharmacology 24:561-7

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