Complement and Traumatic Brain Injury

补体和创伤性脑损伤

• 批准号: 7870812
• 负责人: MARK S. KINDY
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870812
• 关键词: Animals; Anti-Inflammatory Agents; Attenuated; Behavioral; Binding; Biological Availability; Blast Cell; Caring; Cell Adhesion Molecules; Clinical; Complement; Complement 3; Complement 3d Receptors; Complement Activation; Complement Inactivators; Complex; Conflict (Psychology); Craniocerebral Trauma; Deposition; Development; Devices; Disease; Event; Experimental Models; Generations; Goals; Homeostasis; Host Defense; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Leukocytes; Life; Link; Medical; Mus; Pathogenesis; Pathway interactions; Patients; Play; Process; Production; Recombinants; Recovery; Recovery of Function; Reporting; Risk; Role; Safety; Site; Soldier; Spinal cord injury; Techniques; Therapeutic; Therapeutic Effect; Tissues; Traumatic Brain Injury; Veterans; activation product; attenuation; base; central nervous system injury; combat; complement pathway; complement system; cytokine; design; improved; in vivo; mouse model; novel strategies

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.

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，活跃战斗地区的士兵因创伤性脑损伤（TBI）和脊髓损伤（SCI）而返回。由于战区存在简易爆炸装置（IED），美国士兵面临更大的危险、爆炸力过大和脑外伤。为了提供更好的护理，我们需要了解 TBI 的发病机制并制定更好的治疗策略。 创伤性脑损伤 (TBI) 会引发一系列病理生理事件，导致继发性损伤并决定功能恢复的程度。尽管 TBI 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着关键作用。补体系统在许多炎症和缺血性疾病的发病机制中发挥着关键作用，最近的证据表明它在继发性 TBI 中也发挥着重要作用。该提案旨在增强我们对 TBI 中补体激活发生机制的理解，并且表明需要更好地理解此类机制对于开发新的更有效的疗法至关重要。目前正在对各种系统性补体抑制剂作为抗炎剂进行治疗研究，但对其功效和安全性仍存在担忧。补体激活产物对于宿主防御和免疫稳态机制很重要，系统性补体抑制可能会损害补体的保护和免疫调节作用。在这种情况下，中枢神经系统损伤已被证明具有免疫抑制作用，对于有感染风险的患者来说，通过全身补体抑制来进一步抑制免疫可能不是最佳选择。 拟议研究的长期目标是开发一种基于减轻 TBI 后补体依赖性继发性损伤的神经保护策略。我们开发了一种策略，将补体抑制剂靶向补体激活和损伤位点，并表明，与传统的全身抑制方法相比，靶向补体抑制剂在体外以及缺血性损伤和 SCI 实验模型中的有效性高 10-20 倍补充。我们假设，我们将补体抑制剂靶向 TBI 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，并提供安全且高效的治疗。靶向补体抑制将通过使用由与补体抑制剂连接的靶向部分组成的可溶性重组嵌合分子来实现。补体抑制剂将是小鼠 Crry（抑制补体途径的早期）或 CD59（抑制途径的晚期）。靶向部分是补体受体 2 (CR2) 的片段，它与沉积在补体激活位点的 C3 的长寿命降解产物结合。除了治疗终点之外，我们还将利用在补体级联中不同点发挥作用的靶向补体抑制剂来研究临床环境中的疾病机制。我们将确定不同补体激活产物的产生与细胞因子产生、粘附分子表达、白细胞浸润和激活以及损伤之间的体内关系。如果这些研究成功，将有助于更好地了解 TBI 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。 该提案的具体目标是：1）表征与 TBI 小鼠模型相关的炎症途径。 2) 确定TBI中补体激活的机制。 3) 确定 TBI 对补体 3 (C3) 缺陷小鼠的影响。 4) 确定补体抑制剂对减轻 TBI 损伤的功效。 公共卫生相关性： 创伤性脑损伤对于退伍军人事务部尤为重要。随着复杂防弹衣和先进医疗技术的出现，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）导致创伤性脑损伤（TBI）和脊髓损伤（SCI）的发生率增加。越来越多的美国士兵因头部外伤和脊髓损伤而返回，而我们仍然无法提供足够的治疗。该提案的总体目标是研究 TBI 所涉及的机制，以复制海湾地区冲突中与战斗相关的伤害。 TBI 设备将用于在小鼠模型中创建损伤，并对动物的损伤、行为变化以及治疗对恢复的影响进行研究。