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

补体系统是构成免疫系统中心组成部分的蛋白质的集合。 参与先天免疫和获得性免疫。补体系统的一个功能是宿主防御和 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。这种病理性的激活 互补是，也将继续是我的主要研究重点。我活动的总体目标是 为了更好地了解补体介导的损伤机制，开发安全有效的治疗方法 基于对补体的靶向抑制。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，它是如何传播损伤的，以及它是如何调节后续修复的 中风、创伤性脑损伤和带血管的复合同种异体移植。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是 继续开发和表征补体抑制剂，用于治疗应用 并作为工具用于研究临床相关的补体依赖型疾病机制 条件。一个特别的重点将是开发损伤部位靶向补体抑制剂，以提供 比全身性补体抑制更安全、更有效的选择。中开发的一些方法 这些实验室正在进行商业开发。更具体地说，目前和计划开展的研究活动包括： 创伤性脑损伤：1.研究不同的补体途径和激活产物 促进脑外伤后的神经炎症和促进神经退变。2.研究时空关系 大鼠颅脑损伤后补体沉积模式及其与神经炎性标志物的关系 补体充足而补体抑制的大脑。3.研究补体-小胶质细胞轴的作用 在颅脑损伤后神经元和突触的变性丢失中。4.调查神经炎性反应 慢性创伤性脑损伤中的神经变性和认知功能减退。5.调查视觉功能障碍 与TBI相关。 卒中：1.研究年龄和吸烟对急性和慢性补体依赖的影响 卒中后神经炎症，并探讨补体调节在年龄和性别中的作用 吸烟的合并症。2.研究补体和修饰的神经炎性反应是如何诱导的 按年龄和香烟烟雾暴露与当前护理再灌注治疗标准相互作用 康复。3.研究补体抑制作为中风的慢性治疗策略，以及补体抑制在治疗中风中的作用 在受伤和修复方面都是互补的。4.探讨全身性补体活性与 急性卒中患者血清补体激活天然IgM抗体水平与卒中预后的关系 有并存的疾病。 带血管复合同种异体移植：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 并描述了一种新的双功能靶向方法，用于将补体抑制剂输送到血管内 复合同种异体移植。3.研究脑死亡、补体和早期同种异体移植损伤如何影响急性 血管化复合同种异体移植排斥反应及所需免疫抑制治疗参数。4. 探讨补体和同种异体免疫及其调节对小鼠后肢功能恢复的影响 免疫抑制治疗的背景。5.开发一种新的方法来防止移植物排斥反应 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.