The integrating theme of this project is that three classes of gene products are intimately involved with modulating injury of neurons and glia following hypoxia/ischemia and, more specifically, that altering expression of these gene products can attenuate such hypoxic/ischemic damage. The program aims to define more precisely the roles of SOD, bcl-2 and hsp70 in modifying the detrimental effects of oxidative stress on cerebral neurons/glia and determining the ultimate survival or death (necrotic versus apoptotic) of these cells. The selection of these three genes for intense study reflects their potential therapeutic value, as well as the important information their investigation will yield regarding basic biologic mechanisms of ischemic cell death in central nervous tissue. The experimental results of this project could potentially lead to novel strategies for treating clinical stroke, as well as other traumatic and degenerative neurologic disorders showing a similar pathogenesis. The Program includes three interrelated projects utilizing advanced molecular biology techniques, including gene transfer therapy and transgenic technology in several paradigms of both in vitro and in vivo neuronal and glial injury. The protective potential of the three different genes will be examined using gene transfer in neuronal and glial cultures, and in transgenic and knockout cultures under anoxic and aglycemic conditions (Project 1). The neuroprotective benefit of the same three classes of genes will be studied in several models of ischemia using gene transfer in genetically normal rats (Project 2), as well as investigating protection against ischemia in transgenic or knockout rodents (Project 3). The Vector Core 9Core C) will prepare viral vectors to be used in the gene transfer experiments of Projects 1 and 2. The Transgenic Core (Core B) will produce transgenic mice and rats, as well as knockout mutants to be used in Projects 1 and 3. The Administrative Core (Core A) will provide grant management, financial administration, statistical consultation, centralized purchase, seminar arrangements, clerical assistance, and scientific consultation through Advisory Committees.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS037520-02
Application #
6165264
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jacobs, Tom P
Project Start
1999-07-15
Project End
2004-02-29
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$1,004,828
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
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
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
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

Showing the most recent 10 out of 117 publications