We propose a Systems Biology approach to map transcriptional regulatory networks and related signaling pathways that are altered in Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion leading to a polyglutamine extension in the huntingtin protein and is characterized by problems with movement, cognition and behavioral function. Although the genetic basis for the disease is clear, the mechanism by which huntingtin causes the observed symptoms remains enigmatic. Our approach is based on the hypothesis that many of the genes previously linked to HD through proteomic and genetic screens are connected through signaling pathways to many of the transcriptional changes that have been reported in HD studies. Identifying these pathways would provide critical new insights into the molecular changes that underlie the disease, and could lead to novel therapeutic strategies. We have recently developed a technique for identifying such signaling pathways through a combination of computational and experimental methods.
In Specific Aim 1 we will map out changes in recruitment of transcriptional regulatory proteins because these proteins lie at the interface between the signaling and expression changes.
In Specific Aim 2 we will computationally identify signaling changes "upstream" of these regulators that link the transcriptional changes to the genetic and proteomic data. If successful, this approach will advance knowledge of the etiology of HD and provide a powerful new method for studying many human diseases.

Public Health Relevance

We propose a systems biology approach to understanding the molecular changes that occur in Huntington's disease. This project uses high-throughput experiments and computational modeling to reveal pathways that are altered in the disease and that may lead to new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089903-05
Application #
8611929
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$467,469
Indirect Cost
$175,856
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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