Corneal damage from TBI (traumatic brain injury)

About This Grant

ABSTRACT Traumatic brain injury (TBI) often leads to vision loss and damage to cranial dura mater (CDM), the outermost brain meningeal covering, which regulates the brain’s metabolic waste and cerebrospinal fluid outflow. The incidence of TBI- related disability in men is 2.2 times higher than in women, but reasons for this disparity remain unknown. CDM shares sensory innervation with cornea through trigeminal ganglion system forming anatomo- physiological link between easily accessible cornea and unreachable CDM. Our resent collaborative study identified a connection between corneal injury and alterations in the connective tissue and microvasculature of the CDM. Additional pilot data support these findings and show delayed time-dependent corneal damage in response to mild TBI. Importantly, we reveal the involvement of decorin, a small leucine-rich extracellular matrix proteoglycan, in cornea-CDM crosstalk post injury. Our recent novel in vivo findings and human clinical literature led us to hypothesis that TBI-induced insult to CDM leads to neuroinflammatory alterations in cornea via ophthalmic division of the trigeminal ganglion supplying sensory innervation to cornea and this pathological event is modulated by the decorin. The primary goal of the project is to identify mechanism of TBI/CDM-injury to cornea and test if decorin can serve as a therapeutic target to regulate this pathological process. The results of study will lead to identification of mechanisms mediating corneal dysfunction post TBI/CDM injury and uncovering of strategies for treating TBI/CDM-induced corneal damage resulting vision loss in vivo. The two Specific Aims will test novel hypothesis and accomplish goal of current project. Specific Aim 1 elucidates how TBI/CDM-injury alters neuroinflammatory responses in cornea in vivo using a well-established mouse model. Specific Aim 2 tests if decorin has therapeutic potential to regulate TBI/CDM-mediated pathological responses in cornea in vivo using decorin-knockout (loss-of-function) mouse model and insult to CDM. Our multidisciplinary team has cornea and CDM experts with experience in TBI/CDM-injury in vivo mouse model, and has established methods, published protocols, and vast expertise in corneal and CDM research with experience in clinical eye imaging, quantitative computer-based image analysis, and molecular techniques. The scientific impact of project is high as successful will (a) advance understanding of the anatomo-physiological connection between cornea and CDM provided by trigeminal system, (b) unveil neuroinflammatory link between cornea and CDM, (c) improve clinical diagnostic approach for pathophysiology of cornea and TBI disorders associated with the activation of trigeminal system, (d) fill knowledge gaps regarding the sex-based differences in anatomo-physiological connection between cornea and CDM, and (e) allow us to collect pilot data for R01 application to extend this research.