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Characterization of epithelial-neural communication

上皮神经通讯的表征

基本信息

批准号：
9240592
负责人：
Kathryn Marie Albers
金额：
$ 53.34万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240592
关键词：
Action Potentials Activation Analysis Affect Afferent Neurons Avil Behavior Behavioral C Fiber Cells Characteristics Coculture Techniques Code Communication Complex Cutaneous Electrophysiology (science)Epidermis Epithelial Epithelial Cells Exhibits Fiber Freund&apos s Adjuvant Ganglia Generations Genetic Models Genetic Transcription Glutamates Growth Factor Halorhodopsins Heterogeneity Hyperalgesia Hypersensitivity Inflammation Inflammatory Keratin Knowledge Lasers Light Lighting Measures Mechanics Mediating Modeling Mus Nature Nerve Nerve Fibers Nervous system structure Neurons Nociceptors Outcome Pain Pathologic Pattern Peripheral Peripheral Nerves Pharmacology Phenocopy Phenotype Physiological Plasticizers Preparation Process Production Property Proteins Reverse Transcriptase Polymerase Chain Reaction Role Sensory Skin Spinal Cord Spinal Ganglia Stimulus Temperature Testing Touch sensation Transgenic Mice afferent nerve behavior measurement behavioral response cell type cutaneous sensory neurons experimental study genetic approach inflammatory pain insight keratinocyte mouse model optogenetics public health relevance relating to nervous system response sensory stimulus

项目摘要

DESCRIPTION (provided by applicant): The transduction of cutaneous stimuli has been previously thought to be solely a function of sensory fibers. It is now recognized that production of growth factors and neuroactivators (e.g., NGF, ATP, ACh, glutamate) by epidermal keratinocytes can have a profound effect on this process. To unravel these complex interactions and advance our understanding of the mechanisms regulating neural-keratinocyte communication, we developed optogenetic mouse models in which light activated channelrhodopsin (ChR2) is targeted to cutaneous sensory neurons. Light stimulation of the skin of these mice was found to elicit a robust nocifensive behavioral response. Electrophysiological analysis of this activation using a skin-nerve-ganglia and spinal cord ex vivo preparation showed preferential activation of C-fiber nociceptors. Thus, blue-laser light penetrates the epidermis and activates ChR2 at levels that depolarize peripheral nerve terminals. Interestingly, light activation of some neurons did not elicit response properties identical to those obtained using direct mechanical or thermal stimulation of the skin. We hypothesized this lack of a full response reflected a missing stimulus from the skin. We therefore isolated mice in which ChR2 was targeted exclusively to K14 keratin expressing keratinocytes. Remarkably, light stimulation of keratinocytes expressing ChR2 evoked changes in behavioral and electrophysiologic response properties of cutaneous sensory neurons. We also found that different subtypes of cutaneous afferents are activated at different levels suggesting heterogeneity in skin-neural communication. Using these new genetic models we propose three specific aims to advance these findings: Aim 1 experiments will examine how light-induced release of neuroactivators (e.g., ATP) from ChR2- expressing keratinocytes activates subtypes of primary sensory afferents. Aim 2 will determine how light activation of ChR2 or halorhodopsin expressed by subtypes of sensory afferents or keratinocytes affects afferent response properties. We will also determine how this activation compares to mechanical and/or thermal stimulation of the skin. Aim 3 experiments will determine the contribution of changes in keratinocytes and sensory neurons to thermal and mechanical hyperalgesia in a model of inflammatory pain. These studies will determine if hyperalgesia is caused by changes in primary afferents, skin keratinocytes or both. The ability to control activation of either keratinocytes or sensory afferents will provide new insights into how the skin and sensory nervous system communicate under normal and inflamed conditions.