In addition to cell protection, promoting post-ischemic angiogenesis and functional recovery has emerged as a potential approach for the treatment of stroke. Tumor necrosis factor receptor- alpha( (TNF-alpha) and nuclear factor kappa B (NF-(B) play critical roles in many pathological and physiological events including blocking apoptosis and promoting angiogenesis. These two actions of the TNF-(-NF-(B cascade, however, have not been well defined in the ischemic brain. Based on previous and preliminary experiments, we propose to test the hypothesis that the TNF-(-NF-(B pathway-mediated anti-apoptotic effect and angiogenesis promote neurovascular remodeling and functional recovery after a small focal ischemia in the barrel cortex. This unique stroke model to be tested in wild type mice and gene-knockout mice lacking TNF-( receptor TNFR1 (p55), TNFR2 (p75), or NF- kappa B p50 will allow us to examine the TNF-(-NF-(B cascade in the context of pathological and functional changes in the well-defined sensory-motor cortex of the whisker-barrel pathway selectively damaged by the clinically important small stroke.
Aim 1. Anti-apoptotic effects of the TNF-(-NF-(B cascade after barrel cortex stroke. We hypothesize that the TNF-(-NF-(B pathway is protective against ischemia-induced apoptosis in neurons and vascular endothelial cells. The effects of selectively eliminating and changing TNFR1, TNFR2, and NF-(B signals on apoptosis will be evaluated after the focal ischemia.
Aim 2. Angiogenesis stimulated by the TNF-(-NF-(B cascade after barrel cortex stroke. We will examine the possibility that the TNF-(-NF-(B pathway is involved in increasing angiogenic signals such as vascular endothelial growth factor (VEGF) and angiopoietins that promote angiogenesis after ischemia. We will also test the hypothesis that negative consequences such as carcinogenesis can be averted by modulating angiogenic activity.
Aim 3. Functional recovery promoted by the TNF-(-NF-(B cascade after barrel cortex stroke. It is expected that TNF-(-NF-(B -cascade-induced cell survival and angiogenesis promote neurovascular plasticity and long-term functional recovery after the barrel cortex stroke. The cause-effect relationship between these events will be evaluated in wild type and gene-knockout mice by blocking and stimulating the signals identified in Aim 1 and 2. This investigation aims to elucidate the relationship between the TNF-(-NF-(B cascade, apoptosis, and angiogenesis, and functional recovery after a small ischemic stroke that represents 38% of clinical cases. Results from this study are expected to provide novel strategies for promoting functional restoration after focal ischemic stroke.
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