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Neutrophil driven recovery from traumatic and ischemic optic neuropathy

中性粒细胞驱动创伤性和缺血性视神经病变的恢复

基本信息

批准号：
10001989
负责人：
Andrew Robert Sas
金额：
$ 17.95万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001989
关键词：
Acute Adoptive Transfer Adult Animal Model Anti-Inflammatory Agents Axon Blindness CD14 gene Cell Death Cell Nucleus Cell Survival Cell Therapy Cell Wall Cell surface Cells Chemotactic Factors Clinical Coculture Techniques Crush Injury Cytoprotection Data Development Eye Failure Future Glaucoma Goals Greater sac of peritoneum Immune Immunological Models Immunomodulators Immunotherapy In Vitro Individual Inflammation Inflammatory Response Injections Injury Interleukin-8B Receptor Ischemia Ischemic Optic Neuropathy Lead Leukocytes Measures Mediating Modeling Mus Natural regeneration Nerve Crush Nervous System Physiology Neurites Neuronal Injury Neurons Neutrophil Infiltration Neutrophilic Infiltrate Ophthalmology Optic Nerve Optic Nerve Injuries Optic Neuritis Optics Outcome Outcome Study Output Pathologic Pathway interactions Patients Perfusion Peripheral Pharmacological Treatment Phenotype Population Property Recovery Research Retina Retinal Ganglion Cells Role Savings Scientist Secondary to Study models Testing Time Transcript Translating Trauma Ursidae Family Vision Visual Visual system structure Yeasts Zymosan arginase axon regeneration axonopathy base career cell injury chemokine chemokine receptor experimental study genetic profiling immunoregulation improved in vitro Assay in vivo innovation migration monocyte nanoparticle neuroinflammation neuron loss neuroprotection neutrophil novel novel therapeutic intervention optic nerve disorder posterior eyeball chamber prevent recruit regenerative repaired response retinal ganglion cell regeneration trafficking

项目摘要

Abstract Axonopathy is an early and prominent pathological feature of optic neuritis, ischemic optic neuropathy, glaucoma, and traumatic optic nerve injury. Permanent loss of vision in all of these conditions is secondary, in large part, to a failure of retinal ganglion cells (RGC), the output neurons of the optic nerve, to survive and regenerate their axons. There is a dire need to develop novel therapeutic interventions that overcome barriers to repair in the adult CNS and promote RGC survival and 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 transcripts for arginase-1 and CD206. In preliminary studies we demonstrated that zymosan elicited Ly6GlowCD14+ neutrophils stimulate neurite outgrowth of dissociated RGC in co-cultures in vitro. Furthermore, adoptive transfer of purified 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. The overall goals of the current proposal are to increase our understanding of the pathways that underlie the intraocular accumulation and function of reparative Ly6GlowCD14+ neutrophils, and to assess their efficacy in an alternative model of optic nerve damage. In Aim 1, we will interrogate the factors that promote the intraocular accumulation of Ly6GlowCD14+ neutrophils in our model. We hypothesize that the chemokines involved differ from those that orchestrate the trafficking of mature, conventional neutrophils. In Aim 2, we will determine the role of the arg1+ monocytes, that are recruited to the eye following the initial entry of Ly6GlowCD14+ neutrophils, in RGC protection and axon regeneration. In Aim 3, we will test our hypothesis that Ly6Glow CD14+ neutrophil mediated ocular repair translates to another model of RGC injury, secondary to ischemia. 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 optic trauma or other conditions characterized by optic neuropathy.

摘要轴索病是视神经炎、缺血性视神经病变，青光眼和外伤性视神经损伤。在所有这些情况下，永久性视力丧失都是次要的，大部分原因是视网膜神经节细胞（RGC），视神经的输出神经元，无法存活，再生轴突迫切需要开发新的治疗干预措施，以克服障碍修复成年CNS并促进RGC存活和轴突再生。这里提出的研究是基于我们发现了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+，积聚在眼后房或腹膜腔在局部施用酵母细胞壁提取物酵母聚糖之后。这些中性粒细胞具有环状结构，细胞核，并表达高水平的转录物的CD 206和CD 206。在初步研究中，证实酵母多糖引起Ly 6 GlowCD 14+中性粒细胞刺激解离的RGC的神经突生长在体外共培养中。此外，过继转移纯化的酵母聚糖引起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。目前提案的总体目标是增加我们对眼内积聚的基础途径和修复功能的理解 Ly 6 GlowCD 14+中性粒细胞，并评估其在视神经损伤替代模型中的疗效。在Aim中 1，我们将询问促进Ly 6 GlowCD 14+中性粒细胞在我们的眼内积聚的因素。模型我们假设所涉及的趋化因子不同于那些协调运输的趋化因子。成熟的常规中性粒细胞在目标2中，我们将确定arg 1+单核细胞的作用，即在Ly 6 GlowCD 14+中性粒细胞初始进入后招募到眼睛，在RGC保护和轴突再生中起作用。再生在目标3中，我们将检验我们的假设，即Ly 6 Glow CD 14+中性粒细胞介导的眼部修复，转化为另一种继发于缺血的RGC损伤模型。我们希望，我们的研究将最终导致基于细胞的创新疗法和/或免疫调节疗法的发展。具有神经保护/再生特性的药物，可恢复视神经病变患者丧失的神经功能创伤或以视神经病变为特征的其他病症。