The long term goal of our studies is to identify genetic factors that underlie molecular events involved in the regulation of rest:activity behavior in the mouse. We employed forward genetics approach to identify single gene mutations that cause gross changes in activity levels or organization of rest:activity cycles. These changes may be due to general metabolic or developmental defects, or caused by anomalies in neurobiological processes, such as the circadian system and regulation of sleep. We have established an integrated and nested phenotypic protocol, which will allow us to characterize novel mutations on several levels; molecular, neuropathological, electrophysiological and behavioral.
Our aims are:
Aim 1) Genetic characterization, mapping and positional cloning of rest/activity mutants, identified by random ENU (N-ethyl-N-nitrosourea) mutagenesis; 1) Aim 2) Characterization of sleep patterns in selected rest:activity mutants;
Aim 3) Determination of the specificity of rest:activity disturbances;
Aim 4) Microarray analysis will be used to define downstream pathways disrupted by the mutant gene. Initially, this project includes genetic and phenotypic characterization of two mutations, one with an effect on circadian period (Rooster), and second, Bedlam, associated with a decreased amplitude of the circadian rhythms. Our hypothesis is that a subset of rest:activity mutations will uncover novel genes involved in the regulation of sleep and their interaction with the other neurobiological processes, such as those that underlie learning and memory or circadian system. Human orthologs of loci defined by these single gene mutations may represent additive or interactive contributions to the polygenic component of inherited psychiatric and sleep disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064867-06
Application #
6616233
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Winsky, Lois M
Project Start
2001-09-01
Project End
2007-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
6
Fiscal Year
2003
Total Cost
$341,217
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104