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A novel inflammatory cell with neuroprotective and neuroregenerative properties

一种具有神经保护和神经再生特性的新型炎症细胞

基本信息

批准号：
9900003
负责人：
Benjamin M Segal
金额：
$ 27.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900003
关键词：
Adoptive Transfer Adult Alzheimer&apos s Disease Autologous Axon Biological Process Bone Marrow Brain Cell Death Cell Nucleus Cell Survival Cell Therapy Cell Wall Cell surface Cells Central Nervous System Diseases Chronic Clinical Crush Injury Data Development Disease Eye FRAP1 gene Future Generations Glaucoma Goals Greater sac of peritoneum HIF1A gene Harvest Human Hypoxia Immune Immunomodulators In Vitro Individual Inflammation Inflammatory Injections Injury Kinetics Knockout Mice Knowledge Lead Ligands Liquid substance Maintenance Mediating Mediator of activation protein Microglia Modeling Multiple Sclerosis Mus Nerve Crush Nerve Regeneration Nervous System Physiology Neuraxis Neurites Neurologic Neurologic Deficit Neurons Neutrophilic Infiltrate Optic Nerve Outcome Pathogenicity Pathologic Pathway interactions Patients Pattern recognition receptor Peripheral Nervous System Phenotype Property Proteins Proteomics Protocols documentation Recombinants Reporting Research Research Project Grants Retina Retinal Ganglion Cells Role Signal Transduction Site Source Spinal Ganglia Spinal cord injury Stabilizing Agents Sterility Stimulus Testing Therapeutic Intervention Time Transcript Transforming Growth Factor beta Transforming Growth Factors Translating Traumatic Brain Injury Traumatic CNS injury Ursidae Family Vision Yeasts Zymosan arginase axon injury axon regeneration axonopathy base central nervous system injury conditional knockout dectin 1 disability experimental study genetic approach immunomodulatory therapies in vivo innovation monocyte neuronal cell body neuronal survival neutrophil novel novel therapeutic intervention novel therapeutics optic nerve disorder posterior eyeball chamber prevent receptor regenerative repaired response spinal cord and brain injury subcortical ischemic vascular disease therapy design transcription factor transcriptome sequencing

项目摘要

Axonopathy is an early and prominent pathological feature of many central nervous system (CNS) disorders, including brain and spinal cord trauma, optic neuropathy, Multiple Sclerosis, early stage Alzheimer’s disease, and subcortical ischemia. Poor clinical outcomes in all of these neurological conditions are due, in large part, to the limited regenerative capacity of adult CNS neurons, including retinal ganglion cells (RGC, the neurons that give rise to the optic nerve). There is a dire need to develop novel therapeutic interventions that overcome barriers to repair in the adult CNS and promote axonal regrowth. The studies proposed here are based on our discovery of a novel subset of pro-regenerative neutrophils, characterized by the cell surface phenotype Ly6GlowCD14+, that accumulate in the posterior chamber of the eye or the peritoneal cavity following local administration of the yeast cell wall extract, zymosan. These neutrophils bear a ring-form nucleus and express high levels of pattern recognition receptor, dectin-1, as well as transcripts for arginase-1 and CD206. In preliminary studies we demonstrated that adoptive transfer of zymosan-elicited Ly6GlowCD14+ neutrophils directly into the vitreous of mice with optic nerve crush (ONC) injury is sufficient to rescue RGC from cell death and to stimulate the regrowth of severed RGC axons. Furthermore, conditioned media harvested from cultures of Ly6GlowCD14+neutrophils induce neurite outgrowth of dissociated RGC and dorsal root ganglion neurons in vitro. The overall goal of the current proposal is to elucidate the pathways that underlie the differentiation, survival and mechanism of action of these unconventional reparative neutrophils, and to leverage the knowledge gained for the development of immunomodulatory therapies that mitigate, or even reverse, damage to CNS neurons and axons. In Aim 1 we will test our hypothesis that transforming growth factor (TGF)- drives the differentiation of Ly6GlowCD14+ neutrophils in vivo following the administration of zymosan. In Aim 2 we will determine the role of hypoxia induced factor (HIF)-1 in the stabilization, survival and biological functions of Ly6GlowCD14+ neutrophils. In Aim 3 we will optimize protocols for the generation of pro-regenerative neutrophils from bone marrow precursors ex vivo. Selected neutrophil lines will be infused into mice with ONC injury to assess their efficacy as an autologous cellular therapy. In addition, we will use proteomic and genetic approaches to characterize the soluble factors present in Ly6Glow neutrophil-conditioned media that are responsible for enhanced neurite outgrowth. A future direction will be to administer candidate neuroregenerative factors to mice with axonopathy as disease modifying agents. We are hopeful that the data generated by our study will ultimately lead to the development of innovative cell based therapies and/ or immunomodulatory drugs with neuroprotective/ regenerative properties that restore lost neurological functions in patients with CNS trauma or other conditions characterized by axonopathy.

轴突病是许多中枢神经系统（CNS）疾病的早期和突出的病理特征，包括脑和脊髓创伤、视神经病变、多发性硬化、早期阿尔茨海默病，和皮质下缺血。所有这些神经系统疾病的临床结果不佳，在很大程度上是由于成年CNS神经元，包括视网膜神经节细胞（RGC，产生视神经）。迫切需要开发新的治疗干预措施，修复成年中枢神经系统的障碍，促进轴突再生。这里提出的研究是基于我们的发现一种新的促再生中性粒细胞亚群，其特征在于细胞表面表型 Ly 6 GlowCD 14+，在局部免疫后积聚在眼后房或腹膜腔中。施用酵母细胞壁提取物酵母聚糖。这些中性粒细胞具有环形核，并表达更高水平的模式识别受体，dectin-1，以及转录物的转录酶-1和CD 206。在我们的初步研究表明酵母多糖诱导的过继转移Ly 6 GlowCD 14+中性粒细胞直接注入具有视神经挤压（ONC）损伤的小鼠的玻璃体中足以拯救RGC免于细胞死亡并刺激切断的RGC轴突再生。此外，从培养物收获的条件培养基的Ly 6 GlowCD 14+中性粒细胞诱导分离的RGC和背根神经节神经元的轴突生长，体外当前提案的总体目标是阐明分化的基础途径，这些非常规修复性中性粒细胞的存活和作用机制，并利用为开发减轻甚至逆转损伤的免疫调节疗法而获得的知识中枢神经系统神经元和轴突。在目标1中，我们将测试我们的假设，即转化生长因子（TGF）-β驱动酵母聚糖给药后Ly 6 GlowCD 14+中性粒细胞的体内分化。在目标2中，确定缺氧诱导因子（HIF）-1（HIF-1 α）在稳定、存活和生物学功能中的作用， Ly 6 GlowCD 14+中性粒细胞。在目标3中，我们将优化用于产生促再生的来自骨髓前体的离体嗜中性粒细胞。将选定的中性粒细胞系输注到患有ONC的小鼠中以评估其作为自体细胞疗法的功效。此外，我们将使用蛋白质组学和遗传学方法，表征Ly 6 Glow嗜水气单胞菌条件培养基中存在的可溶性因子的方法负责促进神经突生长未来的方向将是管理候选人神经再生因子作为疾病修饰剂用于患有轴突病的小鼠。我们希望这些数据我们的研究产生的最终将导致创新的基于细胞的疗法的发展和/或具有神经保护/再生特性的免疫调节药物，其恢复丧失的神经功能 CNS创伤或其他以轴突病为特征的疾病患者。