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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Stanford University
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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
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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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