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，在活跃的战斗地区的士兵正在返回创伤性脑损伤（TBI）和脊髓损伤（SCI）。由于战斗地区的简易爆炸装置（IED），美国士兵面临更大的危险，过度的爆炸力和创伤性脑损伤。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）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。虽然TBI后发生的过程是复杂的，但炎症被认为在发生的进行性退行性事件中起关键作用。补体系统在许多炎症和缺血性疾病的发病机制中起着关键作用，最近的证据表明它在继发性TBI中也起着重要作用。该建议旨在提高我们对TBI中发生补体激活的机制的理解，并且建议需要更好地理解这种机制对于开发新的和更有效的治疗方法至关重要。各种全身性补体抑制剂目前正在作为抗炎剂进行治疗研究，但仍存在关于其功效和安全性的担忧。补体激活产物对于宿主防御和免疫稳态机制是重要的，并且全身性补体抑制可损害补体的保护和免疫调节作用。在这种情况下，CNS损伤已被证明是免疫抑制性的，并且通过全身补体抑制的进一步免疫抑制在有感染风险的患者中可能不是最佳的。 所提出的研究的长期目标是开发一种基于减弱TBI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将补体抑制剂靶向补体激活和损伤位点的策略，并且已经表明，与抑制补体的常规全身方法相比，靶向补体抑制剂在体外和缺血性损伤和SCI的实验模型中的有效性高10-20倍。我们假设，我们的新策略，靶向补体抑制剂的网站TBI将提高生物利用度，需要全身抑制补体，并提供一个安全和高效的治疗。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（抑制补体途径早期）或CD 59（抑制途径晚期）。靶向部分将是补体受体2（CR2）的片段，其结合沉积在补体活化位点的C3的长寿命降解产物。除了治疗终点外，我们还将利用在补体级联反应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。我们将确定体内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关系。如果这些研究成功，它们将导致更好地理解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治疗的最佳靶点。 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)目的：探讨创伤性脑损伤时补体激活的机制。3)目的：研究脑外伤对补体C3缺陷小鼠的影响。4)确定补体抑制剂对减轻TBI损伤的疗效。 公共卫生关系： 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）导致创伤性脑损伤（TBI）和脊髓损伤（SCI）的发病率增加。越来越多的美国士兵带着头部创伤和脊髓损伤回国，我们仍然无法提供适当的治疗。该提案的总体目标是研究TBI中涉及的机制，这些机制将复制海湾地区冲突中与战斗有关的伤害。TBI装置将用于在小鼠模型中产生损伤，并将研究动物的损伤、行为变化和治疗对恢复的影响。