A cytokine-activated cascade is proposed to underlie neurodegenerative changes in the human CNS in a variety of diverse situations ranging from those with a well-defined genetic basis (Down's Syndrome) to head injury to aging (Alzheimer's disease). The hypothesis is that associated with this diversity of neuropathological conditions is an array of glial interactions common to all. The overall goal is to evaluate key components of the proposed cytokine cascade in well established models in this laboratory in which numbers and types of glia can be altered in a known fashion. Animal models in which glial populations in the spinal cord are manipulated with little or no physical invasion of the CNS environment will be used. In one model the sciatic nerve will be injured in order to activate both astrocytes and microglia and to induce proliferation of microglia. This combination of glial responses simulates that noted in neurodegenerative diseases in humans. A second model will involve depletion of these glial populations by exposure of the lumbosacral spinal cord to X-rays followed by injury to the sciatic nerve. The glial-depleted state present at the time of the added challenge, sciatic injury, should result in an alteration in the cytokine-activated cascade. Another model will permit comparisons between neural injuries known to result in failed regeneration (sciatic nerve axotomy) vs. successful regeneration (sciatic nerve crush). Glial responses differ morphologically between these two conditions, and aspects of the cascade are anticipated to differ also. The final model will involve a direct alteration of the glial composition of the spinal cord by transplantation of purified, cultured astrocytes or microglia into the glia-depleted environment of the irradiated cord at the time of sciatic nerve injury. Together, these animal models provide a powerful range of control of glial composition in vivo. Transplantation of the individual cell types has the potential of identifying roles of each in the cascade or of interrupting the cascade. Information of this type is fundamental to the design of a strategy(ies) to interfere with or intervene into the propagated cascade.
Showing the most recent 10 out of 140 publications
