BLR&D Research Career Scientist Award Application for Dr. Stephen Tomlinson

补体系统是构成免疫系统的中心成分的蛋白质的集合 参与先天免疫和适应性免疫。补体系统的一个功能是宿主防御， 破坏病原体，但在某些条件下，补体被异常激活，导致 补体系统的破坏力被重定向到自身组织。这种病理性激活 补充是，并将继续是，我的主要研究重点。我活动的终极目标是 更好地了解补体介导的损伤机制，并开发安全有效的治疗方法 基于补体的靶向抑制。目前，在可预见的未来，我的重点将是 研究补体是如何被激活的，它如何传播损伤，以及它如何调节损伤后的修复。 中风、创伤性脑损伤（TBI）和血管化复合同种异体移植。这些都是 与退伍军人健康和医疗保健高度相关的研究。在这些调查中增加的一个主题将 继续开发和表征补体抑制剂，用于治疗应用 并用作在临床相关条件下研究补体依赖性疾病机制的工具， 条件一个特别的重点将是开发损伤部位靶向补体抑制剂， 比全身性补体抑制更安全和更有效的选择。2004年制定的一些办法 该实验室正在进行商业开发。更具体地说，目前和计划的研究活动是： 创伤性脑损伤：1。研究不同的补体途径和激活产物 导致TBI后的神经炎症并促进神经变性。2.调查时空 脑外伤后补体沉积模式及其与神经炎性标志物的关系 补体充足和补体抑制的大脑。3.研究补体-小胶质细胞轴的作用 在脑外伤后神经元和突触的神经退行性丧失中的作用。4.研究神经炎症介导 慢性创伤性脑损伤中的神经变性和认知下降。5.研究视觉功能障碍， 关于TBI 中风：1.研究年龄和吸烟对急性和慢性补体依赖性 脑卒中后神经炎症，并研究补体调节在年龄和 吸烟合并症2.研究补体和修饰的神经炎症反应如何诱导 年龄和香烟烟雾暴露与当前标准的再灌注治疗相互作用， 康复活动. 3.研究补体抑制作为中风的慢性治疗策略，以及 在损伤和修复中的互补。4.研究全身补体活性与 急性脑卒中患者血清补体激活天然IgM抗体水平与脑卒中预后的关系 合并症 吻合血管的同种异体复合材料移植：采用小鼠肢体移植模型：1. 探讨补体和供体脑死亡在移植物缺血再灌注损伤中的作用。2.发展 并表征了一种用于将补体抑制剂递送至血管化的 复合同种异体移植物。3.研究脑死亡、补体和早期同种异体移植物损伤如何影响急性 血管化复合同种异体移植物排斥反应和所需免疫抑制治疗的参数。4. 研究补体和同种异体免疫及其调节如何影响 免疫抑制治疗的背景。5.开发一种新的方法来预防移植排斥反应， 最小化或消除对全身免疫抑制的需要。

The complement system is a collection of proteins that constitute a central component of the immune system involved in both innate and adaptive immunity. One function of the complement system is host-defense and the destruction of pathogens, but under certain conditions complement is aberrantly activated, resulting in the destructive force of the complement system being redirected toward self-tissue. This pathological activation of complement is, and will continue to be, my primary research focus. The over-arching goals of my activities are to better understand complement-mediated injury mechanisms, and to develop safe and effective therapeutics based on targeted inhibition of complement. Currently, and for the foreseeable future, my focus will be to investigate how complement is activated, how it propagates injury, and how it modulates repair following stroke, traumatic brain injury (TBI), and vascularized composite allograft transplantation. These are all areas of research highly relevant to Veteran health and healthcare. An added theme throughout these investigations will continue to be the development and characterization of complement inhibitors, for both therapeutic application and for use as tools to investigate complement-dependent disease mechanisms under clinically relevant conditions. A particular focus will be the development of injury-site targeted complement inhibitors that provide safer and more effective option than systemic complement inhibition. Some of the approaches developed in the laboratory are in commercial development. More specifically, current and planned research activities are: Traumatic Brain Injury: 1. Investigate how the different complement pathways and activation products contribute to neuroinflammation and promote neurodegeneration after TBI. 2. Investigate the spatiotemporal pattern of complement deposition after TBI and the relationship with neuroinflammatory markers in complement-sufficient and complement-inhibited brains. 3. Investigate the role of a complement-microglial axis in the neurodegenerative loss of neurons and synapses after TBI. 4. investigate neuroinflammation-mediated neurodegeneration and cognitive decline in chronic traumatic brain injury. 5. Investigate visual dysfunction as it relates to TBI. Stroke: 1. Investigate the effects of age and smoking on acute and chronic complement-dependent neuroinflammation after stroke, and investigate the effect of complement modulation in the setting of age and smoking co-morbidities. 2. Investigate how complement and a modified neuroinflammatory response induced by age and cigarette smoke exposure interact with the current standard of care reperfusion therapies and rehabilitation. 3. Investigate complement inhibition as a chronic treatment strategy for stroke, and the role of complement in both injury and repair. 4. Investigate the correlation between systemic complement activity and serum levels of complement activating natural IgM antibodies with stroke outcomes in acute stroke patients with co-morbidities. Vascularized composite allograft transplantation: Use mouse models of limb transplantation to: 1. Investigate the role of complement and donor brain death in ischemia reperfusion injury to grafts. 2. Develop and characterize a novel dual function targeting approach for delivery of complement inhibitors to vascularized composite allograft. 3. Investigate how brain death, complement and early allograft injury affect acute vascularized composite allograft rejection and parameters of required immunosuppressive treatment. 4. Investigate how complement and alloimmunity, and their modulation, affect hindlimb functional recovery in the context of immunosuppressive treatment. 5. Develop a novel approach to prevent graft rejection while minimizing or eliminating the need for systemic immunosuppression.