This competitive renewal of my KO2 award reflects a natural progression of my scientific development, first as a child psychiatrist and then as a molecular biologist. From the beginning of my career as a research fellow in psychiatry and in molecular biology, and more recently as a faculty member in the Yale Child Study Center, the focus of my research has been on understanding underlying mechanisms in signaling pathways within the basal ganglia. Disruption of the normal signal transduction pathways within this region occurs in a number of neuropsychiatric disorders, including Tourette's syndrome and obsessive compulsive disorder, as well as being the site of action of the unwanted side effects of the major neuroleptics. The central goal of the proposed investigation is to study the structure and function of a family of protein tyrosine phosphatases, termed STEP. The STEP family is specifically expressed in the CNS, and within the brain is found enriched within neurons of the basal ganglia, amygdala, nucleus accumbens and related structures. The family consists of both cytosolic and membrane-associated isoforms, as well as truncated variants that lack an active catalytic site. Recent work in the lab has identified several substrates of STEP. STEP regulates the tyrosine phosphorylation level of NMDA receptor subunits, the MAP kinase proteins, ERK1/2, and the tyrosine kinase, Fyn. Striking features of STEP include the findings that it contains a MAP kinase binding domain, PEST sequences, polyproline-rich sequences, and two transmembrane domains. We hypothesize that these domains target STEP to subcellular compartments, determine substrate specificity, and enzymatic activity. We have recently demonstrated that STEP is itself phosphorylated at two regulatory serines in a dopamine/D 1/cAMP/PKA pathway. STEP is dephosphorylated in response to glutamate signaling. Additional investigations are now needed that are beyond my expertise in molecular biology. Specifically, there are three areas of career development that I have arranged over the course of the next five years. These include the identification of additional proteins that are substrates of STEP, continued work on the neurotransmitter pathways that regulate STEP activity through phosphorylation/dephosphorylation, and the identification of the kinases and phosphatases that phosphorylate STEP, and their sites. STEP knock-out mice will also be characterized. The proposed investigations will be done in the supportive environment of the Child Study Center with its commitment to cliniclaly informed basic science research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001527-09
Application #
7158556
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Asanuma, Chiiko
Project Start
1998-06-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
9
Fiscal Year
2007
Total Cost
$127,332
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Dabrowska, Joanna; Hazra, Rimi; Guo, Ji-Dong et al. (2013) Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis. Biol Psychiatry 74:817-26
Lebowitz, Eli R; Motlagh, Maria G; Katsovich, Liliya et al. (2012) Tourette syndrome in youth with and without obsessive compulsive disorder and attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 21:451-7
Braithwaite, Steven P; Stock, Jeffry B; Lombroso, Paul J et al. (2012) Protein phosphatases and Alzheimer's disease. Prog Mol Biol Transl Sci 106:343-79
Xu, Jian; Kurup, Pradeep; Nairn, Angus C et al. (2012) Striatal-enriched protein tyrosine phosphatase in Alzheimer's disease. Adv Pharmacol 64:303-25
Olausson, P; Venkitaramani, D V; Moran, T D et al. (2012) The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity. Neuroscience 225:1-8
Saavedra, Ana; Giralt, Albert; Rué, Laura et al. (2011) Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity. J Neurosci 31:8150-62
Briggs, Stephen W; Walker, Jeffrey; Asik, Kemal et al. (2011) STEP regulation of seizure thresholds in the hippocampus. Epilepsia 52:497-506
Hicklin, Tianna R; Wu, Peter H; Radcliffe, Richard A et al. (2011) Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase. Proc Natl Acad Sci U S A 108:6650-5
Zhang, Yongfang; Kurup, Pradeep; Xu, Jian et al. (2011) Reduced levels of the tyrosine phosphatase STEP block ? amyloid-mediated GluA1/GluA2 receptor internalization. J Neurochem 119:664-72
Leckman, James F; King, Robert A; Gilbert, Donald L et al. (2011) Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 50:108-118.e3

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