Immune responses in traumatic RGC death



 DESCRIPTION (provided by applicant): Traumatic injuries of the nervous system, such as traumatic brain injury (TBI), spinal cord injury (SCI) and traumatic optic neuropathy (TON), are major causes of death and disability in the USA and major challenges for the healthcare of veterans. In addition to the primary injury, secondary injuries, which occur after the primary injury dramatically worsens the damage and cause about 40% of TBI deaths. Because little can be done to reverse the primary injury, the primary aim of the treatment is to prevent secondary injury induced neuronal death. One of the major secondary injuries of TBI, SCI and TON is glutamate excitotoxicity, the pathological process by which neurons are damaged and eventually killed by excessive stimulation of glutamate receptors. Therefore, effectively minimizing or preventing glutamate excitotoxicity will reduce the secondary injury to neurons. In addition, glutamate excitotoxicity also plays critical roles in many other neurodegenerative diseases, such as glaucoma, the leading cause of blindness in the world, including veteran population. Both TON and glaucoma specifically injure retinal ganglion cells (RGCs). Because RGCs are the only cells relaying the visual signals from the eyes to the brain, loss of RGCs will result in an irreversible loss of vision and no effective treatments are currently available. Therefore, preventing RGCs from death in TON and glaucoma is crucial to preserve vision. Understanding the mechanisms which control the vulnerability of RGCs to glutamate excitotoxicity, TON or glaucoma will help us to develop treatment strategies to prevent RGC death in these diseases. Recent studies have shown that immune molecules play important roles in neuron repair and cell death in CNS diseases. In the retina, the receptors of major histocompatibility complex (MHC) class I molecules, T-cell receptor, (TCR) and their associated proteins are expressed by RGCs. Mutation of these molecules compromised RGC dendrite and axon structure and increased the vulnerability of RGCs to glutamate excitotoxicity while up-regulated MHCI expression in motor neurons significantly promoted the recovery of locomotor abilities after SCI. These findings strongly support the possibility that MHCI/TCR could protect RGCs from death. In this study, we plan to characterize the vulnerability of RGCs to glutamate excitotoxicity and optic nerve crush (ONC), investigate the roles of TCR in the regulation of RGC vulnerability, and determine the therapeutic potential of activation of TCR for the prevention of RGC death. The first goal of this study is to determine the contribution of a key molecule of TCR, CD3, to the vulnerability of RGCs. Our preliminary results showed that different subtypes of RGCs have different vulnerability to glutamate excitotoxicity and RGC vulnerability to glutamate excitotoxicity is dramatically increased in CD3-/- mice. We will further characterize the vulnerability of four subtypes of RGCs to glutamate excitotoxicity and ONC, and the contribution of CD3to RGC vulnerability. The second goal is to determine the therapeutic potential of overexpressing CD3 to protect RGCs. Our preliminary results demonstrated that expressing CD3 in RGCs of CD3-/- retinas restored the RGC dendritic defects, suggesting the reversibility of CD3-mediated effects on RGCs. We plan to further determine whether the resistance of RGCs can be enhanced by over-expressing the gene encoding CD3. The third goal of this study is to determine the therapeutic potentials of CD3 activating molecules to protect RGCs. It has been demonstrated that CD3 could be activated by exogenous CD3 activating molecules in vitro. We will further determine if the exogenous CD3activating molecules work synergistically with the over-expression of CD3 to protect RGCs. Overall, this study will identify the role of MHCI-TCR in the regulation of the vulnerability of RGCs to pathological insults, and test the potential of using MHCI/TCR mediated mechanisms to protect RGCs from death in diseases. Although RGCs are used as a model in this study, the results could provide important insights into the neuronal death of other areas of CNS and, therefore, have important implications in neuronal protection following traumatic injuries in the CNS.