Several lines of evidence suggest that mutant huntingtin affects gene transcription by sequestering transcription activating and repressing proteins. This does not explain the gene expression changes that occur before mutant huntingtin is detectable in the nucleus, nor does it account for transcription changes caused by abnormal signaling from damaged afferent neurons. The overall aim of this application is to test the hypothesis that the earliest gene expression changes in Huntington's disease (HD) reflect a response of the neuron to misfolded huntingtin protein and to abnormal signaling between afferent and target neurons. To accomplish this the investigator proposes two Specific Aims 1) use mice and cell culture models that express mutant huntingtin protein in eitherthe nucleus orthe cytoplasm to determine how cells transcriptionally respond to each and 2) use mice that express mutant huntingtin protein in eitherafferent neurons ortarget neurons to determine transcriptional responses in neurons. The transcriptional responses will be correlated with pathogenic changes that occur in response to the transgenes. This will generate information and tools needed to further model and test early processes in Huntington's disease. Our long-term goal is to identify early pathogenic events in Huntington's disease in order to provide rational targets for the development of prophylactic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042157-03
Application #
6617995
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Oliver, Eugene J
Project Start
2001-08-15
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$432,500
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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