Role of plasmacytoid dendritic cells in corneal nerve health and regeneration

浆细胞样树突状细胞在角膜神经健康和再生中的作用

基本信息

批准号：
9208776
负责人：
Pedram Hamrah
金额：
$ 20.63万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208776
关键词：
Adoptive Transfer Affect Anatomy Anterior Biological Preservation Bone Marrow Brain-Derived Neurotrophic Factor Burr hole procedure Cell physiology Cells Coculture Techniques Cornea Corneal Stroma Critical Pathways Dendritic Cells Development Diphtheria Toxin Disease Enzyme-Linked Immunosorbent Assay Epithelial Esthesia Eye Eye diseases Family Fiber Flow Cytometry Functional disorder GDNF gene Health Herpetic Keratitis Immune Immunofluorescence Immunologic Inflammatory Injection of therapeutic agent Keratitis Knowledge Link Maintenance Measures Mediating Messenger RNA Modeling Morbidity - disease rate Morphology Mus Myelogenous Natural regeneration Nerve Nerve Fibers Nerve Growth Factors Nerve Plexus Nerve Regeneration Nervous System Trauma Neurites Neurodegenerative Disorders Neurons Neuropeptide Receptor Pathologic Peripheral Nervous System Diseases Play Process Property Protein Tyrosine Kinase Proteins Quantitative Reverse Transcriptase PCR Recovery of Function Regulation Role Sensory Signal Transduction Somatostatin Receptor Source Staining method Stains Structure of trigeminal ganglion Tachykinin Receptor Time Tissues Transgenic Organisms Transplanted tissue Trigeminal nerve structure Tubulin VIPR2 protein Vision Wild Type Mouse Wound Healing adaptive immune response blink reflexes density eye dryness glial cell-line derived neurotrophic factor immune function in vivo intravenous injection macrophage melanocortin receptor nerve injury nerve supply neurotrophic factor neurotrophin 4 novel therapeutic intervention novel therapeutics ocular surface prevent public health relevance receptor reconstitution tumor vasoactive intestinal peptide 2 receptor

项目摘要

DESCRIPTION (provided by applicant): Corneal nerve dysfunction is the pathophysiologic basis of many ocular surface diseases, causing considerable morbidity, including neurotrophic keratitis and dry eye disease and therefore corneal nerve health is a prerequisite for the maintenance of vision. Despite the traditional point of view that immune cells are deleterious for nerve regeneration, recent evidence suggests that immune cells can show beneficial effects in neuronal regeneration. For instance, macrophages and conventional dendritic cells are among the key players in providing a neuro-protective and neuro-trophic microenvironment for nerve regeneration following nerve damage. Despite recent evidence on neuro-protective and neuro-regenerative functions of immune cells, the role and source of endogenous neurotrophic molecules in the cornea remains elusive. Moreover, the impact of recently identified plasmacytoid dendritic cells (pDCs), a vital subset of immune cells that reside in the anterior stroma just beneath sub-basal corneal nerve plexus of cornea, remains to be determined. These cells orchestrate and link innate and adaptive immune responses and are implicated in the induction of tolerance to transplanted tissues or tumors. Our preliminary results suggest that pDCs are vital in the maintenance and function of corneal nerves, as we demonstrate that local depletion of pDCs in the cornea leads to abrupt and severe nerve loss and diminishment of corneal sensation. Our hypothesis is that pDCs contribute to maintenance, function, and regeneration of nerves through secretion of neurotrophic molecules. Our specific aims include evaluating the significance of pDCs on corneal nerve maintenance and health as well as studying the impact of pDCs on neural regeneration in the cornea following nerve damage. Our fresh perspective on how pDCs contribute to regulation of corneal nerve microenvironment holds promise of amplifying our knowledge far beyond the current state on the cross talk between nerve fibers and immune cells in the cornea and the impact of such cross talk on corneal nerve health and function. Furthermore, this application suggests in vivo approaches for assessing significance of corneal pDCs, in nerve protection and regeneration. Therefore, this proposal will elucidate the neuro-protective and neuro-regenerative properties of pDCs, may result in novel therapeutic approaches, and is potentially applicable in tissues other than cornea and conditions in which neuro-regeneration is vital, including traumatic nervous system injuries, neurodegenerative diseases, and peripheral neuropathies.

描述（由适用提供）：角膜神经功能障碍是许多眼表疾病的病理生理基础，导致考虑发病率，包括神经营养性角膜炎和干眼病，因此角膜神经健康是维持视觉的先决条件。尽管传统的观点是免疫细胞正在删除神经再生，但最近的证据表明，免疫细胞可以在神经元再生中显示出有益的作用。例如，巨噬细胞和常规的树突状细胞是提供神经保护和神经营养的微环境的主要参与者，可在神经损伤后神经再生。尽管最近有证据表明免疫细胞的神经保护和神经再生功能，但内源性神经营养分子在角膜中的作用和来源仍然弹性。此外，最近鉴定出的浆细胞样树突状细胞（PDC）的影响是位于角膜下部角膜下部角膜神经丛中的一个至关重要的免疫细胞子集，仍然待确定。这些细胞协调并连接先天性和适应性免疫回报，并暗示着诱导对移植组织或肿瘤的耐受性。我们的初步结果表明，PDC在角膜神经的维持和功能中至关重要，因为我们证明了角膜中PDC的局部耗竭会导致突然和严重的神经丧失以及角膜感觉的减弱。我们的假设是，PDC通过神经营养分子的分泌有助于维持神经的维持，功能和再生。我们的具体目的包括评估PDC对角膜神经维持和健康的重要性，以及研究PDC在神经损害后对角膜神经变性的影响。我们对PDC如何促进角膜神经微环境如何贡献的新观点有望扩大我们的知识，远远超出了角膜中神经纤维和免疫细胞之间的交叉谈话以及这种交叉对话对角膜神经健康和功能的影响。此外，该应用提出了在神经保护和再生方面评估角膜PDC的重要性的体内方法。因此，该提案将阐明PDC的神经保护和神经再生性能，可能会导致新型的治疗方法，并且可能适用于角膜以外的其他组织，以及神经增长至关重要的条件，其中包括创伤性神经系统，神经减退性疾病，神经性疾病，神经性疾病和外位症。