Role of Endoplasmic Reticulum Stress and Systemic Inflammation in Blunt TBI-Induced Optic Nerve Injury
Abstract
Traumatic brain injury (TBI) is a major cause of injury in American military personnel. TBI caused by blunt head trauma is often associated with vision loss, due to injury of the optic nerve. Such vision loss can be severe. Up to approximately 75% of military personnel with TBI report visual symptoms, and such symptoms lead to significantly reduced quality-of-life measures. In spite of the magnitude of this problem, there are currently no treatments for optic nerve trauma that are backed by scientific evidence. In part, development of such treatments has been hampered by incomplete understanding of the biologic processes that drive ongoing loss of cells in the retina (responsible for detecting and processing light signals, forming the basis of visual perception) and optic nerve (which transmits visual signals from the eye to the brain). Evidence from my laboratory and others suggests that two biologic processes that lead to worsening vision loss after blunt head trauma may include (1) a cellular stress response known as endoplasmic reticulum stress, and (2) generalized inflammation caused by head trauma. The first objective of the proposed research is to determine whether individual components of endoplasmic reticulum stress can be targeted by drugs, thus interrupting part of the degeneration that occurs after the initial injury. The second objective is to determine the role of generalized inflammation in worsening vision after blunt head trauma. To reach these objectives, I will use a mouse model for blunt head trauma, which has prominent visual defects and evidence of damage to the retinas and optic nerves. Characteristics of this model suggest that it is similar in key aspects to human optic nerve injury after head trauma. In the short term, I expect this project to lead to opening new areas of research. The first objective will provide proof-of-concept that targeting specific components of endoplasmic reticulum stress can lead to improvement in visual outcomes after blunt head trauma. This is important because research on endoplasmic reticulum stress in other models or neural injury (such as for stroke) has found that stopping endoplasmic reticulum stress can have helpful or harmful effects. This is likely due to which components of the response are activated or blocked. Thus, my research will clarify what exactly should be targeted after blunt head trauma to improve visual outcomes in future research. The second objective will similarly provide proof-of-concept that targeting peripheral inflammatory processes can improve visual outcomes after blunt head trauma. In addition, it will provide preliminary evidence about the utility of measuring inflammatory responses early after injury, to predict longer- term visual outcomes. Both of these avenues of research will lead to potential new treatments to improve visual outcomes after blunt head trauma. In particular, since both of my objectives will potentially identify new targets for pharmaceutical treatments, the longer-term outcome of this research is expected to be new drugs that will be translatable into human trials and ultimately into treatments for human patients with TBI. Finally, because TBI and associated vision loss is a significant problem in both military and civilian populations, in the long term this research is expected to lead to treatments improving visual health and quality of life in patients with TBI in the military, in Veterans, and in the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110907
Entities
People
- Nathan K. Evanson
Organizations
- United States Army