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Mechanisms of Corneal Neuro-Immune Crosstalk

角膜神经免疫串扰的机制

基本信息

批准号：
10393538
负责人：
Pedram Hamrah
金额：
$ 51.5万
依托单位：
TUFTS MEDICAL CENTER
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：
2018-09-30 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393538
关键词：
Adoptive Transfer Affect Allogenic Antigen Presentation Antigens Autoimmune Axon Axotomy Blood Vessels Cell Adhesion Molecules Cells Cervical Chemotaxis Clinical Coculture Techniques Communicable Diseases Complex Cornea Corneal pain Data Defect Dendritic Cells Denervation Dry Eye Syndromes Effector Cell Electrophysiology (science)Endothelial Cells Enzyme-Linked Immunosorbent Assay Epithelial Exhibits Flow Cytometry Functional Magnetic Resonance Imaging Ganglionectomy Gene Expression Gene Proteins Herpesvirus 1 Homeostasis Immune Immune response Immune system Immunity Immunomodulators In Vitro Inflammation Inflammatory Keratitis Keratoplasty Kinetics Leukocyte Rolling Leukocyte Trafficking Leukocytes Ligation Locomotion Maintenance Measures Mediating Mediator of activation protein Migration Assay Modeling Modernization Molecular Nerve Nerve Regeneration Nervous system structure Neuraxis Neurites Neuroimmune Neurons Neuropathy Neuropeptides Nociceptors Pain Pain Clinics Peripheral Permeability Phenotype Play Population Production Property Protein Isoforms Protein Kinase C Quantitative Reverse Transcriptase PCR Role Sensory Severities Shapes Signal Transduction Source Stimulus Structure of superior cervical ganglion Structure of trigeminal ganglion Surgical sutures Synaptic plasticity System Techniques Time Tissues Toll-like receptors Transgenic Mice Treatment Efficacy Up-Regulation afferent nerve autonomic nerve blink reflexes chemokine clinically relevant cytokine density efficacy evaluation immune activation immune function immunoreaction in vivo leukocyte homing limbal macrophage migration mouse model multiphoton microscopy nerve damage neurotrophic factor neurotropic novel p38 Mitogen Activated Protein Kinase protein expression receptor recruit regeneration function response synaptogenesis uptake wearable sensor technology

项目摘要

SUMMARY Complex interactions between the nervous and immune systems, as main sensors of the body, play a significant role in homeostasis of the cornea. Neurotrophic molecules are vital for maintenance of nerves in peripheral tissues, however, despite our understanding on the impact and diversity of neurotropic molecules in the cornea, their sources and the mechanism through which their production is regulated remains elusive. Our preliminary results suggest that certain populations of leukocytes, in particular plasmacytoid dendritic cells (pDCs), can serve as essential source of neurotrophic molecules. Thus, in this application, we propose evaluating the contribution of each subpopulation of immune cells in providing corneal nerves with the neurotrophic molecules and the signaling mechanism through which activation of immune cells through toll like receptors (TLRs) may alter their neurotrophic properties. Further, we aim to assess if local adoptive transfer of subpopulation of immune cells may enhance nerve regeneration following nerve damage in the cornea. We also aim to determine if resident corneal immune cells regulate function of corneal nerves by depleting each subpopulation of the resident corneal leukocyte and assessing electrical conduction of corneal nerves via electrophysiological studies as well as measuring the response to painful stimuli in the pain centers in central nervous system. Next, we propose to study how corneal nerves (both sensory and autonomic) may regulate several steps in immune reaction, from up-regulation of adhesion molecules and increasing the permeability of limbal vessels to recruitment of immune cells to the cornea and their intra-corneal locomotion. We suggest studying how corneal nerves shape multiple functions of immune cells, including capacity of antigen uptake and presentation to effector cells, profile of secretory cytokines, and angiogenic molecules. The application proposes a paradigm shift on how corneal nerves may mediate immunity, and would potentially introduce new immunomodulatory therapeutic strategies and targets for ocular as well as systemic inflammatory, autoimmune, alloimmune and infectious diseases.

总结神经系统和免疫系统作为人体的主要传感器，它们之间的复杂相互作用，在角膜的稳态中起重要作用。神经营养分子对于维持神经系统的功能至关重要。然而，尽管我们了解了外周组织中亲神经分子的影响和多样性，角膜、它们的来源和调节它们产生的机制仍然是难以捉摸的。我们初步结果表明，某些白细胞群体，特别是浆细胞样树突状细胞， pDC（pDCs）可以作为神经营养分子的必需来源。因此，在本申请中，我们提出评价每种免疫细胞亚群在为角膜神经提供免疫刺激中的作用，神经营养分子和信号传导机制，通过该机制，免疫细胞通过Toll样激活受体（TLR）可以改变它们的神经营养特性。此外，我们的目标是评估当地的收养转移，免疫细胞亚群可以增强角膜神经损伤后的神经再生。我们还旨在确定常驻角膜免疫细胞是否通过耗尽每个细胞来调节角膜神经的功能常驻角膜白细胞的亚群和评估角膜神经的电传导，电生理学研究以及测量中枢疼痛中枢对疼痛刺激的反应，神经系统接下来，我们建议研究角膜神经（感觉神经和自主神经）如何调节免疫反应的几个步骤，从上调粘附分子和增加渗透性，角膜缘血管对免疫细胞向角膜的募集及其在角膜内的运动的影响。我们建议研究角膜神经如何塑造免疫细胞的多种功能，包括抗原摄取能力以及对效应细胞的呈递、分泌性细胞因子和血管生成分子的概况。应用提出了一个关于角膜神经如何介导免疫的范式转变，并可能引入新的免疫调节治疗策略和眼部以及全身炎症的靶标，自身免疫性、同种免疫性和感染性疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cutting Edge: Topical Recombinant Nerve Growth Factor for the Treatment of Neurotrophic Keratopathy-Biologicals as a Novel Therapy for Neurotrophic Keratopathy.

尖端：局部重组神经生长因子用于治疗神经营养性角膜病生物学作为神经营养性角膜病的新疗法。

DOI：
10.1097/ico.0000000000002974
发表时间：
2022-06-01
期刊：
Cornea
影响因子：
2.8
作者：
通讯作者：

A novel animal model of neuropathic corneal pain-the ciliary nerve constriction model.

DOI：
10.3389/fnins.2023.1265708
发表时间：
2023
期刊：
FRONTIERS IN NEUROSCIENCE
影响因子：
4.3
作者：
Seyed-Razavi, Yashar;Kenyon, Brendan M.;Qiu, Fangfang;Harris, Deshea L.;Hamrah, Pedram
通讯作者：
Hamrah, Pedram

Immunomodulatory Role of Neuropeptides in the Cornea.

DOI：
10.3390/biomedicines10081985
发表时间：
2022-08-16
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain.

DOI：
10.1016/j.jtos.2020.12.003
发表时间：
2021-04
期刊：
OCULAR SURFACE
影响因子：
6.4
作者：
Dieckmann, Gabriela;Ozmen, M. Cuneyt;Cox, Stephanie M.;Engert, Ryan C.;Hamrah, Pedram
通讯作者：
Hamrah, Pedram

Concurrent ocular pain in patients with neurotrophic keratopathy.