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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：
10239072
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/10239072
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 Genetic 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 Regenerative capacity 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 immunoregulation improved in vitro Assay in vivo innovation migration monocyte nanoparticle nerve damage neuroinflammation neuron loss neuroprotection neutrophil novel novel therapeutic intervention optic nerve disorder posterior eyeball chamber prevent recruit regenerative repair function 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