Intracerebral hemorrhage (ICH) is a devastating stroke. The damage that occurs in brain from ICH is due to the growing hematoma and clot formation that damages the adjacent brain through edema and apoptosis. Though these are distinct pathologic entities that occur following ICH, we have data that they share some common mechanisms. We found that apoptosis in peri-hematoma brain is mediated in part by glutamate excitotoxicity. This led us to the non-receptor tyrosine kinase, pp60-Src (Src) because it potentiates function of NMDA receptors through direct phosphorylation of the NR2A subunit. We found that Src kinase activity increases 4 fold following experimental ICH in rats, the Src family kinase (SFK) member Lyn increases over 21 fold following ICH, and Src inhibitors decrease apoptosis and improve behavioral outcome following ICH. We hypothesize that Src plays a central role in ICH mediated apoptosis and edema: ICH causes thrombin receptor activation of Src that activates NR2A subunits that mediate apoptosis;and ICH activates thrombin receptors which activates HIF and MMPs via Src to produce edema and poor behavioral outcome. These hypotheses are based upon previous studies showing that thrombin mediates the acute brain edema following ICH, and that thrombin activates Src via the thrombin receptor. Therefore, these studies will examine: (a) the effect of ICH on Src;(b) thrombin activation of Src;(c) ICH induced phosphorylation of NMDA receptors by Src;(d) Src activation of HIF-1, HIF-1 target genes and MMPs;and (e) the effect of Src blockade on cell survival, edema and behavioral outcome using rat models of intracerebral hemorrhage (ICH). The following aims will be addressed:
Aims #1 a-d: Demonstrate that Src mRNA, Src protein, Src phosphorylation and Src activity increase following ICH. Determine whether thrombin antagonists block these ICH induced changes of Src and whether thrombin and thrombin receptor agonists reproduce the ICH induced changes of Src.
Aim #2. Demonstrate changes of HIF-1, of the HIF-1 target gene VEGF, and the Matrix Metalloproteinases and the phosphorylation state of NMDA receptor subunits after ICH in rats with and with out pharmacological blockade of Src.
Aim #3. Demonstrate that pharmacological inhibition of Src improves cell survival, decreases brain edema and improves behavioral outcome following ICH in rats (a) using a blood infusion model of ICH and (b) using a suture induced vessel rupture model of ICH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054652-05
Application #
8009783
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Utz, Ursula
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$325,850
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Liu, DaZhi; Zhang, Xiong; Hu, BeiLei et al. (2016) Src Family Kinases in Brain Edema After Acute Brain Injury. Acta Neurochir Suppl 121:185-90
Liu, Da Zhi; Sharp, Frank R; Van, Ken C et al. (2014) Inhibition of SRC family kinases protects hippocampal neurons and improves cognitive function after traumatic brain injury. J Neurotrauma 31:1268-76
del Zoppo, Gregory J; Sharp, Frank R; Heiss, Wolf-Dieter et al. (2011) Heterogeneity in the penumbra. J Cereb Blood Flow Metab 31:1836-51
Liu, Da-Zhi; Sharp, Frank R (2011) The dual role of SRC kinases in intracerebral hemorrhage. Acta Neurochir Suppl 111:77-81
Zhan, Xinhua; Ander, Bradley P; Jickling, Glen et al. (2010) Brief focal cerebral ischemia that simulates transient ischemic attacks in humans regulates gene expression in rat peripheral blood. J Cereb Blood Flow Metab 30:110-8
Liu, Da-Zhi; Tian, Yingfang; Ander, Bradley P et al. (2010) Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab 30:92-101
Zhan, Xinhua; Ander, Bradley P; Liao, Isaac H et al. (2010) Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats. Stroke 41:538-43
Liu, Da-Zhi; Ander, Bradley P; Sharp, Frank R (2010) Cell cycle inhibition without disruption of neurogenesis is a strategy for treatment of central nervous system diseases. Neurobiol Dis 37:549-57
Liu, Da-Zhi; Ander, Bradley P; Xu, Huichun et al. (2010) Blood-brain barrier breakdown and repair by Src after thrombin-induced injury. Ann Neurol 67:526-33
Jickling, Glen C; Zhan, Xinhua; Ander, Bradley P et al. (2010) Genome response to tissue plasminogen activator in experimental ischemic stroke. BMC Genomics 11:254

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