Michael Tytell, PhD - US grants

Neurons function better in the presence of glial cells, but few of the glial molecules responsible for that effect are known because of the difficulty in separating them from axonal molecules. However, that separation can be achieved in the squid giant axon because of its size (typically 3-6 cm long and 0.5 mm in diameter). Recently, this investigator found that one of the glial proteins transferred into the squid axon belongs to the group of heat stress proteins. These proteins are produced in abundance by most cells after acute exposure to metabolic stress. As the proteins accumulate, the cells become more resistant to potentially lethal stress. The discovery of glia-axon transfer of stress proteins represents a potential breakthrough in the understanding of nervous system response to injury because it implies that the glia can provide to the axon proteins designed to keep the axon from dying in the face of trauma. In the squid giant axon, biochemical, immunochemical and morphological techniques will be used to examine the relationship between the synthesis and glia-axon transfer of stress proteins and axonal stress tolerance. Additionally, stress proteins transfer will be compared to the transfer of other glial proteins to determine if there are multiple mechanisms of glia-axon protein transfer. The work described in this research project will show how the stress protein response in nerve tissue can be enhanced. This information may provide a tool that can help to ameliorate the loss of function after central nervous system injury. Potentially, recovery after nervous system trauma could be improved by stimulation of the production of stress proteins or by administering stress proteins. More far-reaching is the possibility that the loss of neurons after physical trauma to the nervous system could be reduced by proper manipulation of the stress protein response.

Damage to retinal photoreceptors as a consequence of accidental exposure to bright light, physical trauma to the eye, or disease is a serious problem because, once the photoreceptors die, they cannot be replaced. At present, little can be done to reduce photoreceptor degeneration following damage. This proposal is designed to investigate the potential influence of a distinctive cellular reaction to acute stress or damage, known as the heat shock or stress response, on photoreceptor stress tolerance. The heat shock response refers to the dramatic increase in the synthesis of a small group of proteins that occurs in most cells when they are under acute stress due to any one of a variety of factors, such as hyperthermia, heavy metal intoxication, or anoxia. The production of those heat shock proteins (HSPs) correlates with the aquisiton of stress tolerance in many cells. Recently, this investigator has shown that the synthesis of HSPs can be stimulated in rat retina by raising its body temperature 4 to 5 degrees C (the equivalent of a high fever) and that, at the same time, the retinal photoreceptors show a dramatic increase in survival after exposure to a damaging intensity of light. The experiments described herein are aimed at determining how to optimize the hyperthermia-induced increase in photoreceptor stress tolerance, whether it can enhance photoreceptor survival after they are damaged, and what specific role the HSPs have, if any, in the capacity of photoreceptors to survive exposure to damaging levels of light.