Delayed Outcome Mechanisms in Chronic Traumatic Optic Neuropathy
Abstract
Vision loss is an important disability associated with traumatic brain injury (TBI). Damage to many parts of the eyes or brain can result in vision loss. One source of vision loss, that is associated with TBI and leads to chronic, often severe vision loss, is traumatic optic neuropathy (TON). TON results from damage to the optic nerve between the eye and the brain, and leads to degeneration of the retina. There are currently no treatments for TON that have been proven effective in clinical trials. In some patients, vision loss from TON improves on its own over time, while in others it worsens over the long term. Of particular importance to this application, there are no treatments used long after injury that can actually improve vision, even though the majority of individuals with current disability experienced head trauma long ago. My laboratory has shown that in a mouse model of head trauma there is selective optic nerve injury. This injury is similar in important respects to TON that occurs in people after TBI. In particular, there are subgroups of individuals in our studies that have either long-term improvement or worsening of nerve degeneration in the optic nerves. However, it is not yet clear whether these changes are associated with significant differences in visual function. We have also found that short exposure to 100% oxygen soon after TON seems to improve early measures of visual function. However, this oxygen exposure may activate retinal cellular stress responses in a delayed fashion. This delayed activation of cellular stress might be a sign that early oxygen exposure has chronic toxic effects on the retina, and therefore on vision. The objectives of this application are to (1) determine whether the variability in long-term tissue responses to injury are due to late improvement or worsening of TON (or, more likely, both); (2) identify cellular pathways that are important for delayed recovery or worsening of TON; (3) determine whether early oxygen exposure is helpful or harmful in the long-term after TON; and (4) correlate measures of visual function and retinal health that can be performed in living animals (or humans) to tissue measures of damage. We will accomplish these objectives through two experimental aims: Aim 1 is to identify cellular pathways that are differentially active in chronic TON and are associated with delayed deterioration. Aim 2 is to identify long- term effects of early oxygen exposure on functional and histologic recovery from experimental TON. We anticipate that in the short term, this research will identify important processes active in cells of the eye that could potentially be changed using a treatment such as a drug. This research will also determine whether early exposure to oxygen might be beneficial in long-term recovery after TON, or whether there are toxic effects of early oxygen exposure. The research in Aim 2 is expected in the short term to lead to an ability to develop clinical studies to test oxygen treatment in patients with head trauma and associated TON. In the long term, successful completion of this research will lead to opening new research into treatments for long-term vision loss from TON. Of particular interest is that there may be treatments that could be started long after an injury to improve long-term visual function after TON. This research aims to identify potential ways to do this in future studies. This research also has the potential to change the standard of care, specifically relating to use of oxygen for early resuscitation after head trauma, particularly if early oxygen exposure either leads to long-term improvements in vision, or has long-term toxic effects on vision. It is also important to note that many of our proposed measures of eye health and visual function (such as retinal imaging, electrophysiology, and pupillary function) are analogous or identical to measures used in clinical practice on people. This similarity
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211075
Entities
People
- Nathan K. Evanson
Organizations
- United States Army