Regulation of Neuroinflammation after Peripheral Nerve Injury

项目摘要 这项拟议的研究结合了分子神经科学和免疫学技术， 研究损伤后神经系统和免疫系统之间的关系。神经系统 分为中枢神经系统(CNS)，包括大脑和脊髓，以及 周围神经系统(PNS)。神经元是神经系统的主要细胞，由3个 部分：细胞体，用于短距离通讯的树突，以及用于 用于远距离通信。在轴突损伤后，三叉神经节有再生的能力，而这是失败的。 发生在中枢神经系统损伤后。这种情况的结果通常是在受伤后出现长期的功能缺陷 大脑和脊髓。神经免疫学领域的研究突出了炎症性疾病的两种情况 中枢神经和三叉神经节损伤后激活和/或持续的通路。这项工作表明 炎症促进三叉神经节再生，而炎症是三叉神经节再生的抑制因素之一。 中枢神经系统。 这项拟议的研究的长期目标是了解 三叉神经节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 将对空间和时间上的响应进行表征。重要的是，使用转基因小鼠模型将 阐明组织常驻免疫细胞和血源性髓系细胞在这一过程中所起的作用 炎性级联反应。此外，尽管坐骨神经损伤模型以再生而闻名 称职，这一能力将通过使用显示瓦勒联失败的Sarm1-/-鼠标行来改变 退化。沃勒变性是损伤后的一种重要的级联反应，发生在 PNS(但不在中枢神经系统)，并帮助清除碎片，使轴突能够再生。这项工作将询问是否 沃勒变性是炎症性级联反应的触发因素，如果这对轴突 重生。 研究生将利用尖端的分子生物学技术来提出这些问题。他们的 这些发现将有助于理解炎症介导的神经修复，并有助于填补 能够提高制定中枢神经系统损伤治疗策略的能力的知识。学生们将成为 由卡林斯基博士直接监督，并将参与实验设计、数据收集、解释、 以及成果的传播。此外，拟议的部分实验将纳入 这是卡林斯基教授的一门课程的实验室组成部分，该课程每年将新增32名学生。 卡林斯基实验室和她班上的本科生和硕士生将能够 对理解免疫介导的神经修复有直接影响的发现。这些 当他们毕业后追求事业和继续深造时，经验将对他们很有帮助。

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.