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

BLR

• 批准号: 10451506
• 负责人: Stephen Tomlinson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451506
• 关键词: Academy; Acute; Affect; Age; Allografting; American; Antibodies; Appearance; Appointment; Area; Autoimmunity; Award; Biological Markers; Biotechnology; Blood; Blood Circulation; Blood Vessels; Brain; Brain Death; Brain Injuries; Cardiovascular system; Cause of Death; Cells; Central Nervous System Diseases; Chronic; Clinical; Collaborations; Collection; Complement; Complement Activation; Complement Inactivators; Country; Deposition; Development; Devices; Disclosure; Disease; Doctor of Philosophy; Eligibility Determination; Face; Faculty; Foundations; Funding; Future; Goals; Graft Rejection; Grant; HIV; Health; Healthcare; Heart; Hepatology; Hindlimb; Host Defense; Immune system; Immunoglobulin M; Immunology; Immunosuppression; Immunosuppressive Agents; Impaired cognition; Inflammation; Injury; International; Investigation; Jail; Joints; Journals; Laboratories; Lead; Legal patent; Limb structure; Malignant Neoplasms; Mediating; Mental Health; Mentors; Mentorship; Military Personnel; Molecular; Names; Natural Immunity; Nature; Nerve Degeneration; Outcome; Paper; Participant; Pathologic; Pattern; Population; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Process; Proteins; Publications; Publishing; Quality of life; Recovery; Recovery of Function; Regulation; Rehabilitation therapy; Reperfusion Injury; Reperfusion Therapy; Research; Research Activity; Research Project Grants; Review Committee; Role; San Francisco; Science; Scientist; Series; Serum; Services; Sheep; Site; Smoking; Soldier; Spinal cord injury; Stroke; Synapses; Therapeutic; Time; Tissues; Training; Transplantation; Transplantation Immunology; Traumatic Brain Injury; United States National Institutes of Health; Veterans; Vietnam; Visit; Work; activation product; acute stroke; adaptive immunity; addiction; age effect; allograft rejection; base; blast trauma; career; central nervous system injury; clinically relevant; comorbidity; complement pathway; complement system; dementia risk; disability; disability risk; doctoral student; effective therapy; experience; exposure to cigarette smoke; facial transplantation; high risk; improved; injury and repair; interest; invention; isoimmunity; limb transplantation; military veteran; mouse model; neuroinflammation; neuron loss; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; post stroke; prevent; programs; rehabilitation research; repaired; research and development; response; spatiotemporal; standard of care; stroke model; stroke outcome; stroke patient; stroke risk; stroke therapy; symposium; therapeutically effective; tool; treatment strategy; visual dysfunction

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.

补体系统是构成免疫系统核心组成部分的蛋白质的集合 参与先天性免疫和适应性免疫。补体系统的功能之一是宿主防御， 消灭病原体，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新定向到自身组织。这种病理性激活 补充是并将继续是我的主要研究重点。我活动的总体目标是 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。目前以及在可预见的未来，我的重点将是 研究补体如何被激活、它如何传播损伤以及它如何调节修复 中风、创伤性脑损伤（TBI）和血管复合同种异体移植。这些都是领域 与退伍军人健康和医疗保健高度相关的研究。这些调查中的一个额外主题将是 继续开发和表征补体抑制剂，用于治疗应用 并用作研究临床相关补体依赖性疾病机制的工具 状况。特别关注的是损伤部位靶向补体抑制剂的开发，该抑制剂可提供 比全身补体抑制更安全、更有效的选择。开发的一些方法 该实验室正在进行商业开发。更具体地说，当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如何 导致神经炎症并促进 TBI 后的神经变性。 2. 考察时空 TBI后补体沉积模式及其与神经炎症标志物的关系 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 TBI 后神经元和突触的神经退行性丧失。 4. 研究神经炎症介导的 慢性创伤性脑损伤中的神经退行性变和认知能力下降。 5. 调查视觉功能障碍 与 TBI 相关。 中风：1.调查年龄和吸烟对急性和慢性补体依赖性的影响 中风后的神经炎症，并研究补体调节在年龄和年龄背景下的影响 吸烟并发症。 2. 研究补体和修饰的神经炎症反应是如何诱导的 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，以及补体抑制的作用 补充损伤和修复。 4. 研究全身补体活性与 补体激活天然 IgM 抗体的血清水平与急性卒中患者的卒中结果 有合并症。 血管化复合同种异体移植：使用肢体移植小鼠模型： 1. 研究补体和供体脑死亡在移植物缺血再灌注损伤中的作用。 2. 开发 并描述了一种新颖的双功能靶向方法，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损伤如何影响急性 血管化复合同种异体移植排斥反应和所需免疫抑制治疗的参数。 4. 研究补体和同种免疫及其调节如何影响后肢功能恢复 免疫抑制治疗的背景。 5. 开发一种新方法来预防移植物排斥反应 最大限度地减少或消除对全身免疫抑制的需要。