The overall goal of this project is to understand the molecular mechanisms of ischemic tolerance in cortical neurons. Neuronal ischemic preconditioning or tolerance is a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia. The signaling mechanisms leading to preconditioning are poorly understood but have the potential for providing important pharmaceutical targets for the treatment of patients at risk for ischemic injury and possibly the treatment of patients suffering from chronic neurodegenerative diseases such as Parkinson's Disease. Ischemia can be modeled in vitro by oxygen-glucose deprivation (OGD). We have recently discovered that OGD preconditioning induces p2 p21ras (Ras) activation in a NMDA receptor- and NO-dependent manner. OGD preconditioning is dependent on Ras activation of the Raf-Mek-Erk pathway. Our observations indicate that activation of the Ras/Erk cascade by NO is a critical mechanism for the development of OGD tolerance in cortical neurons, which may also play an important role in ischemic preconditioning in vivo. To further our understanding of preconditioning it is essential to identify the transcriptional elements that are activated and the new proteins that are responsible for this remarkable neuroprotection. In this project we propose to investigate the role of transcriptional targets of the Ras/Erk signaling cascade with a focus on CREB and Elk activation. We will identify genes that are regulated by preconditioning and determine which genetic changes are responsible for preconditioning. Preconditioning can also be induced by potassium depolarization in an in vitro model of spreading depression. We will investigate whether similar or different mechanisms are responsible for potassium depolarization induced tolerance. We anticipate that this series of investigations will identify endogenous protective mechanisms that ultimately may be harnessed as novel protective strategies against ischemic and traumatic injury as well as chronic neurodegenerative disorders such as Parkinson's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040809-04
Application #
6796758
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
2001-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$367,875
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chi, Zhikai; Byrne, Sean T; Dolinko, Andrew et al. (2014) Botch is a ?-glutamyl cyclotransferase that deglycinates and antagonizes Notch. Cell Rep 7:681-8
Chi, Zhikai; Zhang, Jianmin; Tokunaga, Akinori et al. (2012) Botch promotes neurogenesis by antagonizing Notch. Dev Cell 22:707-20
Alberi, Lavinia; Chi, Zhikai; Kadam, Shilpa D et al. (2010) Neonatal stroke in mice causes long-term changes in neuronal Notch-2 expression that may contribute to prolonged injury. Stroke 41:S64-71
Zheng, Sika; Eacker, Stephen M; Hong, Suk Jin et al. (2010) NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice. J Clin Invest 120:2446-56
Dai, Cheng; Liang, Dong; Li, Huiwu et al. (2010) Functional identification of neuroprotective molecules. PLoS One 5:e15008
Dawson, V L; Dawson, T M (2006) Mining for survival genes. Biochem Soc Trans 34:1307-9
Hong, Suk Jin; Li, Huiwu; Becker, Kevin G et al. (2004) Identification and analysis of plasticity-induced late-response genes. Proc Natl Acad Sci U S A 101:2145-50