Abstract

Glutamate excitotoxicity is the presumed mechanism underlying many neurological disorders including acute ischemia and chronic neurodegeneration. Recent work from our laboratories demonstrated that mice lacking the neural isoform of the stress activated protein kinsase SAPK/JNK (JNK3) has remarkable resistance to kainic acid-induced seizures, AP-1 transcriptional activity and apoptosis of hippocampal neurons. These results strongly suggest that the SAPK/JNK signaling pathway is a critical component in the pathogenesis of glutamate excitotoxicity. Based on this hypothesis, the present proposal comprises two sets of closely related in vitro and in vivo experiments.
Specific Aim I : Mechanism of JNK -mediated glutamate neurotoxicity ( in vitro studies). Keys issues to be addressed include: (1) the JNK - mediated neurotoxicity through gene regulation and de novo biosynthesis; (2) the regulation of intracellular calcium oscillation through JNK signaling; (3) the interplay between JNK - signaling And oxidative stress, (4) the specificity of activation route of JNK signaling. These potential mechanisms will be tested in primary culture of dissociated neurons using a combination of morphological, physiological and biochemical approaches.
Specific Aim II : Neuroprotection of the blockade JNK signaling pathway (in vivo studies) Potential clinical applications of inhibition of the JNK signaling may include: (1) the prevention of ischemic apoptosis; (2) attenuation of chronic glutamate excitotoxicity in amytrophic lateral sclerosis; (3) the prevention of neurodegneration (4) enhanced survival of grafted neurons in transplantation therapy. Preliminary evidence of feasibility has been obtained for each Specific Aim. The potential applications will be tested in experimental models of neuropathology using wildtype and mutant mice lacking the neural-specific JNK3 isoform. In summary, the overall goal of the present proposal is both to understand the mechanism underlying JNK- mediated glutamate neurotoxicity and to test the clinical potential of targeting the JNK signaling pathway for therapeutic intervention.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038296-05
Application #
6637681
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
1999-03-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2005-02-28
Support Year
5
Fiscal Year
2003
Total Cost
$327,938
Indirect Cost

  Institution

Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Benoit, Jamie D; Rakic, Pasko; Frick, Karyn M (2015) Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res 281:1-8
Ayoub, Albert E; Rakic, Pasko (2015) Neuronal misplacement in schizophrenia. Biol Psychiatry 77:925-6
Dominguez, Martin H; Ayoub, Albert E; Rakic, Pasko (2013) POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb Cortex 23:2632-43
Han, Kihoon; Gennarino, Vincenzo Alessandro; Lee, Yoontae et al. (2013) Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev 27:485-90
Arellano, Jon I; Guadiana, Sarah M; Breunig, Joshua J et al. (2012) Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol 520:848-73
Hashimoto-Torii, Kazue; Kawasawa, Yuka Imamura; Kuhn, Alexandre et al. (2011) Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol. Proc Natl Acad Sci U S A 108:4212-7
Liu, Xiuxin; Hashimoto-Torii, Kazue; Torii, Masaaki et al. (2010) Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. J Neurosci 30:4197-209
Rakic, Pasko (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10:724-35
Torii, Masaaki; Hashimoto-Torii, Kazue; Levitt, Pat et al. (2009) Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461:524-8
Burns, Kevin A; Murphy, Brian; Danzer, Steve C et al. (2009) Developmental and post-injury cortical gliogenesis: a genetic fate-mapping study with Nestin-CreER mice. Glia 57:1115-29

Showing the most recent 10 out of 13 publications