Complement and Traumatic Brain Injury

描述(由申请人提供)： 问题和关键问题的陈述最近的报告表明，现役作战地区的士兵正带着创伤性脑损伤(TBI)和脊髓损伤(SCI)返回。由于战区使用简易爆炸装置(IED)，美军士兵面临更大的危险、过度的冲击力和创伤性脑损伤。为了提供更好的护理，我们需要了解脑外伤的发病机制，并制定更好的治疗策略。创伤性脑损伤可引发一连串的病理生理事件，导致继发性损伤，并决定功能恢复的程度。尽管颅脑损伤后发生的过程很复杂，但炎症被认为在发生的进行性退行性事件中发挥了关键作用。补体系统在许多炎症性和缺血性疾病的发病机制中起着关键作用，最近的证据表明它在继发性脑损伤中也起着重要作用。这一建议旨在加强我们对脑外伤中补体激活机制的了解，并提示需要更好地了解这种机制对于开发新的和更有效的治疗方法至关重要。目前，各种全身性补体抑制剂作为抗炎药正在进行治疗研究，但其有效性和安全性仍然令人担忧。补体激活产物对机体防御和免疫动态平衡机制具有重要作用，全身性补体抑制可削弱补体的保护和免疫调节作用。在这种情况下，中枢神经系统的损伤被证明是免疫抑制的，在有感染风险的患者中，通过全身补体抑制进一步的免疫抑制可能并不是最理想的。这项研究的长期目标是开发一种基于减轻脑外伤后补体依赖性继发性损伤的神经保护策略。我们已经开发了一种策略，将补体抑制剂靶向补体激活和损伤的部位，并表明在体外和在缺血性损伤和脊髓损伤的实验模型中，靶向补体抑制剂的效果是传统全身方法抑制补体的10-20倍。我们推测，我们将补体抑制剂靶向于脑损伤部位的新策略将提高生物利用度，消除系统性抑制补体的需要，并提供一种安全和高效的治疗方法。靶向的补体抑制将通过使用可溶性的重组嵌合分子来实现，该嵌合分子由与补体抑制剂相连的靶向部分组成。补体抑制剂将是小鼠CRY(在补体途径的早期抑制)或CD59(在途径的晚期抑制)。靶向部分将是补体受体2(CR2)的一段片段，它与C3的长寿降解产物结合，这些C3沉积在补体激活的部位。除了治疗终点外，我们还将利用在补体级联中不同点起作用的靶向补体抑制剂来研究临床环境中的疾病机制。我们将在体内确定不同补体激活产物的产生与细胞因子的产生、黏附分子的表达、白细胞的渗透和激活以及损伤之间的关系。如果这些研究成功，它们将有助于更好地了解脑外伤后继发性组织损伤的机制，并将确定补体级联中的特定点作为最佳治疗靶点。该提案的具体目的是：1)表征与脑外伤小鼠模型相关的炎症途径。2)探讨脑外伤后补体活化的机制。3)观察脑损伤对补体3(C3)缺乏小鼠的影响。4)探讨补体抑制剂对颅脑损伤的减轻作用。 公共卫生相关性： 创伤性脑损伤对退伍军人事务部特别重要。随着先进的防弹衣和先进的医疗技术的出现，我们能够保护暴露在危险条件下的士兵的生命。最近的报告表明，简易爆炸装置(IED)有助于增加创伤性脑损伤(TBI)和脊髓损伤(SCI)的发生率。越来越多的美国士兵带着头部创伤和脊髓损伤归来，我们仍然无法提供足够的治疗方法。这项提议的总体目标是研究创伤性脑损伤所涉及的机制，这些机制将复制海湾地区冲突中与战斗有关的伤害。脑损伤装置将被用来在小鼠模型中制造损伤，并将研究动物的损伤、行为变化和治疗对康复的影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.