The long term objective of our studies is to identify novel behavioral mutations in mice which may allow the dissection of genetic pathways underlying neurobiological processes. The limited availability of appropriate animal models has hindered research in complex neuropsychiatric illnesses such as schizophrenia, major affective disorders, and sleep disorders. Pharmacologic and surgical manipulations have been used to induce behaviors that simulate aspects of human disorders in laboratory animal models; however, these models represent phenocopies and do not reflect genetic causes of aberrant behavior in the animal. The approach outlined in this proposal involves random mutagenesis of the mouse genome, using a potent mutagen N-ethyl-N nitrosourea (ENU), and screens for abnormal behavioral phenotypes; in particular, disrupted rest: activity behavior and altered acoustic startle response. Novel mutations will be phenotypically characterized based on their chromosomal location and complementation analysis. This project is part of a larger effort-NIH Investigator-Initiated Interactive Research Project (IRPG)- to perform a genome-wide search for dominant behavioral mutations and to saturate a portion of the mouse genome with recessive mutations. A combination of random mutagenesis (IRPG one proposal) with an effort to create deletions (IRPG two proposal) across the 30 cM region on mouse chromosome 5, well characterized at the genetic and molecular level, will allow the identification of recessive mutations in a two generation saturation screen for 2% of the mouse genome. The IRPG effort will allow identification, phenotypic analysis and mapping of development and behavioral mutants as well as identification of mutants whose dominant behavioral anomalies may be due to underlying development, and/or neuroanatomical and neuropathological defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057855-04
Application #
6363700
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Farmer, Mary E
Project Start
1998-03-01
Project End
2003-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
4
Fiscal Year
2001
Total Cost
$322,389
Indirect Cost
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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