Recent progress in the area of stroke research suggests that a number of molecular mechanisms are intimately involved in the evolution of ischemic brain injury. Gene induction has been observed following ischemia, but the exact roles of many are not yet well known. Some gene products are known to be detrimental to the cell while others are felt to be neuroprotective. The goals of this project are to define more precisely the roles of three classes of genes which may play neuroprotective roles. They are: the proto oncogene, bcl-2, antioxidant genes (sod-1 and gspx) and the stress protein, hsp70. In Project 2, we will utilize genetically normal animals and study 3 different in vivo models of ischemia (2 focal and one global models of cerebral ischemia). We will alter gene expression via gene transfer using defective herpes simplex and adenoviral vectors. We will study the limits and conditions under which gene over-expression may improve neuron survival. We hypothesize that injury due to some, but not other kinds of insults will be attenuated with gene product over-expression, and that these observations will offer insight into the pathophysiology of cell death. We will examine whether gene transfer after the onset of injury is neuroprotective, and whether over-expression of Bcl-2 and antioxidant genes are protective against permanent as well as transient focal cerebral ischemia. We will also examine mechanisms underlying neuroprotection, or lack of neuroprotection, by examining the participation of other gene products such as the stress proteins, caspases and Bcl-2 family proteins in response to gene over-expression and cerebral injury. We will also study whether gene over-expression alters generation of superoxide and apoptosis. These novel approaches will hopefully add insight into the complex molecular processes involved in cerebral ischemia and may lead to the development of treatments for stroke and other degenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS037520-02
Application #
6396016
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2000-03-01
Project End
2001-02-28
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$185,329
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Knowland, Daniel; Arac, Ahmet; Sekiguchi, Kohei J et al. (2014) Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82:603-17
Arac, Ahmet; Grimbaldeston, Michele A; Nepomuceno, Andrew R B et al. (2014) Evidence that meningeal mast cells can worsen stroke pathology in mice. Am J Pathol 184:2493-504
Daadi, Marcel M; Hu, Shijun; Klausner, Jill et al. (2013) Imaging neural stem cell graft-induced structural repair in stroke. Cell Transplant 22:881-92
Cheng, Michelle Y; Lee, Alex G; Culbertson, Collin et al. (2012) Prokineticin 2 is an endangering mediator of cerebral ischemic injury. Proc Natl Acad Sci U S A 109:5475-80
Encarnacion, Angelo; Horie, Nobutaka; Keren-Gill, Hadar et al. (2011) Long-term behavioral assessment of function in an experimental model for ischemic stroke. J Neurosci Methods 196:247-57
Horie, Nobutaka; Pereira, Marta P; Niizuma, Kuniyasu et al. (2011) Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells 29:274-85
Andres, Robert H; Horie, Nobutaka; Slikker, William et al. (2011) Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134:1777-89
Andres, Robert H; Choi, Raymond; Pendharkar, Arjun V et al. (2011) The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain. Stroke 42:2923-31
Cheng, Michelle Y; Lee, I-Ping; Jin, Michael et al. (2011) An insult-inducible vector system activated by hypoxia and oxidative stress for neuronal gene therapy. Transl Stroke Res 2:92-100
Arac, Ahmet; Brownell, Sara E; Rothbard, Jonathan B et al. (2011) Systemic augmentation of alphaB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation. Proc Natl Acad Sci U S A 108:13287-92

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