Associate Provost for Research Boston University Medical Campus
NIMH - National Institute of Mental Health	Research Resources

Abstract

Abstract: DESCRIPTION: 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.

Thesaurus Terms:
biological signal transduction, calmodulin dependent protein kinase, enzyme activity, learning, memory, molecular dynamics, molecular genetics
chemical carcinogenesis, enzyme inhibitor, enzyme substrate, hippocampus, mutant, neural information processing, neural plasticity, synapse
behavior test, behavioral /social science research tag, electrophysiology, gene targeting, genetically modified animal, immunocytochemistry, laboratory mouse

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2005
Department:	PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Project Start:	15-MAR-2001
Project End:	28-FEB-2007
ICD:	NATIONAL INSTITUTE OF MENTAL HEALTH
IRG:	ZRG1