The primary focus of these studies is on the role of the glial-derived protein, S100B, in inducing neuronal cell death through the activation of glia following perinatal hypoxia-ischemia (HI). The term 'glial activation' is used to define the process by which glia, especially astrocytes and microglia, respond to insults, injury, or alterations in their environment. Activated glia shows pro-inflammatory cytokines and oxidative stress enzymes. Cell-based and clinical studies have implicated S100B in the initiation and maintenance of a pathologic state of glial activation culminating in neuronal death. A working model based on cell culture experiments, for the sequence of glial activation can be summarized as: S100B --> TNF alpha and IL-11 beta released from microglia --> iNOS induction in astrocytes --> NO generation and neuronal death. Whether this process is recapitulated in vivo is a principal focus of the proposed studies. Our preliminary in vivo data, other cell-based data and clinical observation suggests that S100B is released in response to brain injury and that elevated S100B levels initiate a pathologic process of glial activation culminating in neuronal death or dysfunction. Our hypothesis is that hypoxia-ischemia (HI) in the newborn mouse brain leads to increased glial release of S100B resulting in an increase in glial activation and enhancement of neuronal injury. Our preliminary data suggest that transgenic mice which over-express the S100B protein are more vulnerable to HI injury, showing increased mortality and infarct size.
Our specific Aims are: 1) Characterize the pro-inflammatory glial response after HI using histochemical and molecular techniques; 2) Elucidate the role of St00B in the mechanism of glial-dependent neurologic injury after HI using MRI and immunohistochemical methods; and 3) Determine the effects of pharmacologic inhibition of glial activation on neurologic injury in wild type, S100B transgenic and knockout mice using novel bioavailable protein kinase inhibitors. The convergent pharmacological and genetic approaches to understanding the mechanisms of glial activation in acute brain injury may lead to the identification of new therapeutic targets in perinatal asphyxia.
Showing the most recent 10 out of 13 publications
