The long-term goals of our research are to elucidate the molecular and cellular mechanisms of learning and memory in the mammalian brain. Building on the strength of the successful development of brain region-specific gene knockout technology, we propose to explore a novel bump-and-hole chemical-genetic approach for the study of rapid (seconds-minutes) signaling cascades controlled by various protein kinases and of their functions in learning and memory in the mammalian brain. This novel chemical-genetic approach has two powerful applications: First, it can be used to develop the third-generation gene knockout technology, which combines the specificity of molecular genetics with the reversible, fast kinetics of pharmacology. This chemical based gene knockout technique should permit more precise molecular dissections of the roles of protein kinases in various temporal stages of learning and memory consolidation. Secondly, this novel bump-and-hole approach also offers the unprecedented opportunity to identify the direct substrates of the various kinases, a challenging task so far hindered by complexity of the kinase family and extremely conserved kinase domains. In this proposal, we will focus on two major neural kinases to demonstrate the broad utility of this novel approach. The first set of biochemical and molecular experiments will be performed to systemically identify and analyze their direct downstream substrates. The second set of genetic and behavioral experiments will be carried out to demonstrate the feasibility of the chemical-genetic approach to the study of memory consolidation. Understanding the kinase-triggered molecular cascade events in memory formation may lead to a new strategy for potential therapeutic interventions in the treatment of memory disorders such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH062632-05
Application #
6945616
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Anderson, Kathleen C
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2004-10-15
Budget End
2005-02-28
Support Year
5
Fiscal Year
2004
Total Cost
$432,101
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Wang, Huimin; Feng, Ruiben; Phillip Wang, L et al. (2008) CaMKII activation state underlies synaptic labile phase of LTP and short-term memory formation. Curr Biol 18:1546-54
Osan, Remus; Zhu, Liping; Shoham, Shy et al. (2007) Subspace projection approaches to classification and visualization of neural network-level encoding patterns. PLoS One 2:e404
Cao, Xiaohua; Cui, Zhenzhong; Feng, Ruiben et al. (2007) Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 25:1815-22
Lin, Longnian; Osan, Remus; Shoham, Shy et al. (2005) Identification of network-level coding units for real-time representation of episodic experiences in the hippocampus. Proc Natl Acad Sci U S A 102:6125-30