Statement of the problem and key questions Recent reports indicate that soldiers in active combat regions are returning in with traumatic brain injury (TBI) and spinal cord injury (SCI). Because of improvised explosive devices (IEDs) in combat regions, US soldiers are exposed to greater danger, excessive blast-force and traumatic brain injuries. To provide better care, we need to understand the pathogenesis of TBI and develop better therapeutic strategies. Traumatic brain injury (TBI) initiates a cascade of pathophysiological events that cause secondary injury and determine the extent of functional recovery. Although the processes that occur following TBI are complex, inflammation is considered to play a key role in the progressive degenerative events that take place. The complement system plays a key role in the pathogenesis of many inflammatory and ischemic conditions, and recent evidence indicates it also plays an important role in secondary TBI. This proposal is designed to enhance our understanding about the mechanisms by which complement activation occurs in TBI, and it is suggested that the need for a better understanding of such mechanisms is critical for the development of new and more effective therapeutics. Various systemic complement inhibitors are currently under therapeutic investigation as anti-inflammatory agents, but there remain concerns regarding their efficacy and safety. Complement activation products are important for host defense and immune homeostasis mechanisms, and systemic complement inhibition can compromise the protective and immunomodulatory roles of complement. In this context, CNS injury has been shown to be immunosuppressive, and further immune suppression by systemic complement inhibition may not be optimal in patients at risk of infection. The long term goal of the proposed studies is to develop a neuroprotective strategy based on attenuating complement-dependent secondary damage after TBI. We have developed a strategy to target complement inhibitors to sites of complement activation and injury, and have shown that targeted complement inhibitors are 10-20 fold more effective in vitro and in an experimental models of ischemic injury and SCI compared to conventional systemic approaches to inhibit complement. We hypothesize that our novel strategy to target complement inhibitors to the site of TBI will improve bioavailability, obviate the need to systemically inhibit complement, and provide a safe and highly efficacious therapy. Targeted complement inhibition will be achieved by the use of soluble recombinant chimeric molecules consisting of a targeting moiety linked to a complement inhibitor. Complement inhibitors will be mouse Crry (inhibits early in the complement pathway) or CD59 (inhibits late in pathway). The targeting moiety will be a fragment of complement receptor 2 (CR2) that binds to long lived degradation products of C3 that are deposited at sites of complement activation. In addition to therapeutic endpoints, we will utilize the targeted complement inhibitors that function at different points in the complement cascade to investigate disease mechanisms in a clinical setting. We will determine in vivo relationships between the generation of different complement activation products with cytokine production, adhesion molecule expression, leukocyte infiltration and activation, and injury. If these studies are successful, they will result in a better understanding of the mechanisms of secondary tissue injury after TBI, and will identify a specific point in the complement cascade as an optimum target for therapy.
The specific aims of the proposal are: 1) To characterize the inflammatory pathways associated with the mouse model of TBI. 2) To determine the mechanisms of complement activation in TBI. 3) To determine the effect of TBI in complement 3 (C3) deficient mice. 4) To determine the efficacy of complement inhibitors on attenuation of injury in TBI.
Traumatic brain injury has particular importance for the Department of Veterans Affairs. With the advent of sophisticated body armor and advanced medical techniques we are able to preserve the life of soldiers exposed to hazardous conditions. Recent reports have indicated that improvised explosive devises (IEDs) contribute to an increase in the number of incidences of traumatic brain injury (TBI) and spinal cord injury (SCI). US soldiers are returning in greater numbers with head traumas and spinal cord injuries for which we are still incapable of providing adequate therapies. The overall goal of this proposal is to study the mechanisms involved in TBI that will replicate combat-related injuries seen in the Gulf region conflicts. The TBI device will be used to create an injury in the mouse model and the animals will be studied for injury, behavioral changes and the effect of therapeutics on recovery.
| Hook, Gregory; Jacobsen, J Steven; Grabstein, Kenneth et al. (2015) Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate. Front Neurol 6:178 |
| Novgorodov, Sergei A; Riley, Christopher L; Yu, Jin et al. (2014) Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J Biol Chem 289:13142-54 |
| Hook, Gregory; Yu, Jin; Toneff, Thomas et al. (2014) Brain pyroglutamate amyloid-? is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J Alzheimers Dis 41:129-49 |
