My application for a K02 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 family consists of both cytosolic and membrane-associated isoforms, as well as truncated variants that lack an active catalytic site. A striking feature is that some STEP isoforms contain transmembrane domains, PEST sequences, and polyproline-rich sequences. We hypothesize that these domains provide a mechanism for the subcellular targeting, as well as determining their substrate specificity and enzymatic activity. These hypotheses require additional investigations beyond my expertise in molecular biology. Specifically, there are four areas of career development that I have arranged over the course of the next five years. These include the identification of interacting proteins that form complexes with STEP members using both the yeast 2 hybrid system, as well as affinity chromatography to biochemically purify associated proteins. STEP knockout mice will also be characterized. The proposed investigations will be done in the supportive environment of the Child Study Center with its commitment to clinically 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 #
1K02MH001527-01
Application #
2439004
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1998-06-01
Project End
2003-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
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
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
Venkitaramani, Deepa V; Moura, Paula J; Picciotto, Marina R et al. (2011) Striatal-enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory. Eur J Neurosci 33:2288-98
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

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