Regulation of Neuroinflammation after Peripheral Nerve Injury

周围神经损伤后神经炎症的调节

• 批准号: 10729778
• 负责人: Ashley L Kalinski
• 金额: $ 44.7万
• 依托单位: BALL STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-17 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729778
• 关键词: Acute; Address; American; Anti-Inflammatory Agents; Axon; Axotomy; Biological Assay; Biology; Brain; Cell Communication; Cell Culture Techniques; Cell Reprogramming; Cells; Cellular biology; Central Nervous System; Chronic; Communication; Competence; Crush Injury; Data; Data Collection; Dendrites; Disease; Distal; Education; Educational process of instructing; Environment; Enzyme-Linked Immunosorbent Assay; Experimental Designs; Failure; Fibrinogen; Flow Cytometry; Goals; Immune; Immune response; Immune system; Immunology; Impairment; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Information Dissemination; Infrastructure; Injections; Injury; Intrinsic factor; Knowledge; Laboratories; Lead; Macrophage; Mediating; Medical; Mentors; Methods; Modeling; Molecular; Molecular Biology Techniques; Mus; Myeloid Cells; Natural regeneration; Nerve; Nervous System; Neuroglia; Neurons; Neurosciences; Pathway interactions; Peripheral Nervous System; Peripheral nerve injury; Play; Positioning Attribute; Postdoctoral Fellow; Recovery of Function; Regulation; Reporting; Research; Research Personnel; Rodent Model; Role; Schwann Cells; Signal Transduction; Site; Spinal Cord; Spinal Ganglia; Students; Supervision; System; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transgenic Mice; Traumatic Nerve Injury; Traumatic injury; Universities; Wallerian Degeneration; Wild Type Mouse; Work; axon injury; axon regeneration; career; central nervous system injury; design; experience; experimental study; improved; inflammatory milieu; injured; innovative technologies; mouse model; nerve injury; neural repair; neuroimmunology; neuroinflammation; neuronal cell body; novel therapeutics; prevent; recruit; repaired; sciatic nerve; sciatic nerve injury; single-cell RNA sequencing; undergraduate student; wound healing

Project Summary The proposed research uses a combination of molecular neuroscience and immunology techniques to investigate the relationship between the nervous system and immune system after injury. The nervous system is divided into the central nervous system (CNS), which includes the brain and the spinal cord, and the peripheral nervous system (PNS). Neurons are the main cells of the nervous system and are composed of 3 parts: a cell body, dendrites that are used for short-distance communication, and a single axon which is used for long distance communication. The PNS has the ability to regenerate following axonal injury, while this fails to occur in after injury to the CNS. The result of this is usually long-term functional deficits following injuries to the brain and spinal cord. Work within the neuroimmunology field has highlighted a dichotomy in inflammatory pathways that are activated and/or sustained following injury to the CNS and the PNS. This work suggests that inflammation promotes regeneration in the PNS, while it is one of the inhibitory factors to regeneration in the CNS. The long-term objective of this proposed research is to understand the relationship between inflammation and axon regeneration within the PNS. Using rodent models of sciatic nerve injury, the immune response both spatially and temporally will be characterized. Importantly, use of transgenic mouse models will elucidate the roles that both tissue resident immune cells and blood-borne myeloid cells have during this inflammatory cascade. Further, while the sciatic nerve injury model is well known for being regeneration competent, this competency will be altered by utilizing the Sarm1-/- mouse line that shows a failure in Wallerian degeneration. Wallerian degeneration is an important cascade following injury that occurs very efficiently in the PNS (but not in the CNS), and helps remove debris so the axons can regenerate. This work will ask whether Wallerian degeneration is the trigger for the inflammatory cascade and if this is essential for axons to regenerate. Research students will utilize cutting edge molecular biology techniques to ask these questions. Their findings will contribute to understanding of inflammatory mediated neural repair and help fill in several gaps in knowledge that could improve the ability to develop therapeutic strategies for CNS injuries. Students will be directly supervised by Dr. Kalinski and will participate in experimental design, data collection, interpretation, and dissemination of results. Furthermore, portions of the experiments proposed will be incorporated into the laboratory components of a course taught by Dr. Kalinski that will reach an additional 32 students a year. Undergraduate and master’s students in the Kalinski laboratory and in her class will be positioned to make discoveries that have a direct impact on the understanding of immune mediated neural repair. These experiences will serve them well as they pursue careers and further education after graduation.

项目摘要 拟议的研究结合了分子神经科学和免疫学技术的结合 调查受伤后神经系统与免疫系统之间的关系。神经系统 分为中枢神经系统（CNS），其中包括大脑和脊髓， 周围神经系统（PNS）。神经元是神经系统的主要细胞，由3个组成 零件：一个细胞体，用于短途通信的树突和使用的单个轴突 进行长距离沟通。 PNS具有轴突损伤后再生的能力，而这失败了 在受伤后发生。结果的结果通常是受伤后的长期功能缺陷 大脑和脊髓。神经免疫学领域内的工作突出了炎症的二分法 在CNS和PNS受伤后激活和/或持续的途径。这项工作表明 炎症促进PNS的再生，而它是抑制性因素之一 CNS。 这项拟议研究的长期目标是了解 PNS内的炎症和轴突再生。使用坐骨神经损伤的啮齿动物模型，免疫 在空间和临时的响应都将被表征。重要的是，使用转基因鼠标模型将 阐明组织居民免疫细胞和血源性髓样细胞在此期间具有的作用 炎症级联。此外，虽然坐骨神经损伤模型以再生而闻名 有能力的情况下，将使用SARM1 - / - 鼠标线来改变这种能力，该线显示Wallerian的失败 退化。沃勒（Wallerian）变性是受伤后的重要级联反应，在 PNS（但不在中枢神经系统中），并有助于去除碎屑，使轴突可以再生。这项工作会询问是否 沃勒（Wallerian）变性是炎症性级联反应的触发因素，如果这对于轴突至关重要 再生。 研究专业的学生将利用尖端分子生物学技术来提出这些问题。他们的 调查结果将有助于理解炎症性介导的神经修复，并有助于填补几个空白 可以提高CNS伤害理论策略的能力的知识。学生会 由Kalinski博士直接监督，将参加实验设计，数据收集，解释， 和结果传播。此外，提出的一部分实验将纳入 Kalinski博士教授的课程的实验室组件，该课程每年将增加32名学生。 卡林斯基实验室及其班级的本科生和硕士学生将定位 对理解免疫介导的神经修复有直接影响的发现。这些 经验将在追随者和毕业后进一步的教育时为他们提供良好的服务。