This application is a direct continuation of our previous grant directed at the genetic mapping of QTL controlling seizure-induced cell death susceptibility in the C57BL/6J and FVB/NJ mouse inbred strains, which differ markedly in their susceptibility to seizure-induced cell death. During the initial funding cycle of this program, we identified 3 susceptibility loci for this complex trait (Sicd1-3) through outcross to C57BL/6J and FVB/NJ mice. In the most recent funding cycle, these loci have been confirmed using reciprocal congenic strains and using interval-specific congenic strains, we have successfully narrowed down our Sicd1 locus to a 3.66 Mb interval. In this application, we propose to use the established congenic strains to: 1) identify quantitative trait genes for Sicd1 and determine if allelic differences in our candidate gene in Sicd1 can control seizure-induced cell death susceptibility in mice;2) to define and characterize the role of specific candidate genes for the Sicd2 susceptibility locus using exon expression profiling;and 3) to investigate the epistatic interaction between Sicd1 and Sicd2 QTLs influencing susceptibility to seizure-induced cell death.
In Aim 1, we will identify prospective candidate genes for the Sicd1 locus and determine whether differences in expression of our candidate gene can result in differential susceptibility to seizure-induced cell death by making several different types of transgenic mice.
In Aim 2, we will use existing congenic strains or mice from new, highly informative crosses to further localize and identify the genes responsible for mapping to Sicd2 by recombinational methods combined with transcriptome analysis. Lastly, in Aim 3, we will determine if loci from Sicd1 and from Sicd2 act in a complementary fashion to alter susceptibility to seizure-induced cell death. Taken together, these experiments will elucidate pathways critical for the survival of hippocampal neurons in epilepsy and aid in the identification of candidate seizure-induced cell death modifier genes in the mouse. An understanding of the molecular pathophysiology of this disease is essential to the rational design of therapeutic interventions. As well, the characterization of cell death pathways in epilepsy may provide insights into mechanisms involved in other neurodegenerative disorders in which excitotoxicity plays a central role.

Public Health Relevance

Our studies will identify and characterize the genes responsible for modulating susceptibility to seizure- induced excitotoxic cell death in murine strains. Identification of epilepsy modifier genes will provide insight into the pathogenesis of epilepsy and aid in the development of novel therapeutic targets for the treatment of human epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038696-11
Application #
8209116
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Riddle, Robert D
Project Start
1999-04-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$347,288
Indirect Cost
$132,913
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Schauwecker, Paula Elyse (2014) Susceptibility to seizure-induced excitotoxic cell death is regulated by an epistatic interaction between Chr 18 (Sicd1) and Chr 15 (Sicd2) loci in mice. PLoS One 9:e110515
Schauwecker, P E (2013) Microarray-assisted fine mapping of quantitative trait loci on chromosome 15 for susceptibility to seizure-induced cell death in mice. Eur J Neurosci 38:3679-90
Schauwecker, P Elyse (2012) Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus. Neurobiol Dis 45:297-304
Schauwecker, P E (2011) Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death. Genes Brain Behav 10:100-10
Schauwecker, P Elyse (2011) The relevance of individual genetic background and its role in animal models of epilepsy. Epilepsy Res 97:1-11
Schauwecker, Paula Elyse (2009) The genetics of status epilepticus. Epilepsia 50 Suppl 12:22-4
Gant, John C; Thibault, Oliver; Blalock, Eric M et al. (2009) Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy. Epilepsia 50:629-45
Kong, S; Lorenzana, A; Deng, Q et al. (2008) Variation in Galr1 expression determines susceptibility to exocitotoxin-induced cell death in mice. Genes Brain Behav 7:587-98
Lorenzana, Ariana; Chancer, Zackary; Schauwecker, P Elyse (2007) A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility. Eur J Neurosci 25:1998-2008
Schauwecker, Paula Elyse (2005) Susceptibility to excitotoxic and metabolic striatal neurodegeneration in the mouse is genotype dependent. Brain Res 1040:112-20

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