Central and Peripheral Mechanisms of Corneal Pain

角膜疼痛的中枢和外周机制

• 批准号: 10595408
• 负责人: Pedram Hamrah
• 金额: $ 133.57万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595408
• 关键词: Acute; Address; Affective; Afferent Neurons; Anatomy; Aversive Stimulus; Behavior; Behavioral; Brain Stem; Brain region; Cell Nucleus; Cells; Chronic; Complex; Cornea; Corneal Diseases; Corneal Injury; Corneal pain; Data; Debridement; Disease; Dry Eye Syndromes; Electrophysiology (science); Excision; Eye Injuries; Gene Expression Profile; Genetic Transcription; Health; Homeostasis; Human; Immune; In Situ Hybridization; In Vitro; Inflammation; Injury; Intervention; Knowledge; Lacrimal gland structure; Lateral; Lead; Leukocytes; Ligands; Measures; Messenger RNA; Molecular; Molecular Profiling; Motivation; Mus; Nerve; Neuroimmune; Neurons; Neuropathy; Nociception; Nociceptors; Pain; Pathway interactions; Peripheral; Peripheral Nerves; Physiological; Population; Population Heterogeneity; Property; Regulation; Resolution; Role; Signal Transduction; Structure of trigeminal ganglion; Structure of trigeminal nerve spinal tract nucleus; Tissues; Transcript; base; cell type; chronic pain; epigenomics; experience; experimental study; interdisciplinary approach; nerve damage; nerve injury; nociceptive response; novel; ocular surface; optogenetics; pain behavior; pain model; parabrachial nucleus; receptor; response; response to injury; transcriptome

The cornea is the most densely innervated tissue in the body, and pain is the primary experience resulting from corneal stimulation. While physiological corneal pain (nociceptive pain) protects the eye from injury, inflammation and/or nerve damage can result in prolonged or chronic corneal pain. Corneal afferents represent a diverse population of neurons, with specialized properties related to maintaining ocular health. The full diversity of these neurons, and their responses to injury are unknown. The first set of experiments will determine the mRNA transcript signatures of mouse corneal neurons in the trigeminal ganglion (TG) and their transcriptional responses to corneal injury and compare with cell-type-specific transcriptional and epigenomic signatures of human TG neurons. Corneal afferents are known to project to two main regions in the spinal trigeminal nucleus (Vsp), each with distinct roles in nociception and maintaining corneal homeostasis. We have preliminary data demonstrating an additional projection to the lateral parabrachial nucleus (lPBN), a region critical in regulating complex motivational-affective responses to aversive stimuli. Its contribution to corneal pain is unknown. The second set of experiments will examine central processing of corneal input in the lPBN. We will determine the contribution of corneal->lPBN primary afferent projections to corneal nociceptive responses and the function of lPBN neurons in corneal nociceptive and chronic pain behaviors. Additional studies will perform single-nucleus transcriptome analysis to identify molecular profiles of corneal-activated brainstem neurons, followed by multiplex in situ hybridization to provide spatial resolution in regions that receive direct corneal afferent input. The cornea is also endowed with resident corneal leukocytes (RCLs) residing in close proximity to corneal nerves, suggesting the possibility of neuro-immune crosstalk in the cornea. However, current knowledge is limited on possible direct regulation of RCLs through corneal nerves, or the influence of RCLs on corneal nerve function. The third set of experiments will characterize the cell populations and molecular mechanisms involved in neuroimmune crosstalk resulting in peripheral nerve sensitization in the cornea. Corneal single cell mRNA transcript signatures associated in murine corneal pain models will be used to identify transcriptional changes that underly nociceptor sensitization. Crossing these immune cell transcripts with transcript profiles of corneal afferents will provide evidence for ligand-receptor pairs. In vitro studies will confirm the ability of the identified modulators to sensitize TG neurons, and the functional significance will be assessed using behavior and ex vivo electrophysiology. Employing a multidisciplinary approach, these experiments will provide a comprehensive analysis of cellular and molecular mechanisms of nociceptive and chronic corneal pain, leading to the identification novel pathways and treatments.

角膜是人体内神经支配最密集的组织，疼痛是由角膜引起的主要感受