Analysis of Neuro-Epidermal Interactions

神经表皮相互作用分析

• 批准号: 7924050
• 负责人: ROBERT P ELDE
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924050
• 关键词: Address; Afferent Neurons; Award; Behavioral; Biochemical; Coculture Techniques; Epidermis; Fiber; Figs - dietary; Fluorescence-Activated Cell Sorting; Foundations; Goals; Growth Factor; Hypersensitivity; In Vitro; Knowledge; Lead; Measurement; Mechanics; Mediator of activation protein; Nerve; Nerve Fibers; Neurons; Neuropeptides; Opioid; Pain; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral nerve injury; Physiology; Production; Qualifying; Research; Research Project Grants; Sensory; Signal Transduction; Skin; Stimulus; Structure; System; Therapeutic; United States National Institutes of Health; afferent nerve; base; cytokine; expectation; in vivo; injured; innovation; keratinocyte; nerve injury; nerve supply; neurochemistry; novel; painful neuropathy; programs; protein expression; public health relevance; receptor; receptor expression; research study; response; sensory stimulus; somatosensory; therapeutic target; transmission process

Description (provided by applicant): The interaction of keratinocytes and epidermal nerve fibers has emerged as an important interface in sensory transduction and pain and may be a factor in the mechanisms underlying painful peripheral neuropathies. Keratinocytes express receptors and channels that enable them to "sense" mechanical and thermal stimuli and transmit signals to epidermal nerve fibers through the release of messenger molecules. Growth factors and cytokines secreted from keratinocytes are also likely to impact long-term changes within the sensory neurons that innervate epidermis. Conversely, neuropeptides contained within sensory neurons have the ability to modulate keratinocytes, including their production and secretion of cytokines and growth factors. Partial peripheral nerve injury that leads to neuropathic pain is associated with degeneration of injured nerve fibers and altered function of adjacent uninjured fibers. The impact of altered epidermal innervation on the dynamic neuro-keratinocyte relationship is unknown. The objective of this R21 proposal is to determine the effects of epidermal innervation on keratinocyte protein expression and function. Specific Aim 1 will address the hypothesis that nerve injury-induced changes in innervation will alter keratinocyte protein expression and function. Epidermal innervation and nerve injury- induced hypersensitivity will be correlated with keratinocyte expression of receptors and channels implicated in sensory transduction as well as cytokines known to sensitize sensory neurons. Functional changes in epidermis will be evaluated based on measurement of keratinocyte ATP release. Specific Aim 2 will determine the effects of sensory neurons on protein expression and function of keratinocytes in organotypic culture where neuronal input will be introduced by co-culture with sensory neurons. These experiments will address the hypothesis that selected subsets of sensory neurons will have differential effects on keratinocytes. Biochemical approaches will be used to identify candidate mediators of neuro-keratinocyte signaling. Changes in the dynamic neuro-keratinocyte relationship following nerve injury may contribute to neuropathic pain mechanisms through sensitization of surviving epidermal nerve fibers and changes in keratinocyte transduction of sensory stimuli. Therefore, neuro-keratinocyte interactions and their modulation by nerve injury represent a previously unexplored component of the pathobiological consequences of nerve injury, and their understanding may lead to identification of novel peripheral therapeutic targets for neuropathic pain. PUBLIC HEALTH RELEVANCE: The proposed project will analyze the interaction between two important structures in the transmission of sensory information: sensory nerves and the epidermis of the skin. These studies will identify a pattern of keratinocyte changes associated with nerve injury that will provide a foundation for in-depth analysis of the contribution of neuro-keratinocyte interactions to pain. Manipulation of these interactions may be able to provide a peripherally restricted therapeutic strategy.

描述（由申请人提供）：角质形成细胞和表皮神经纤维的相互作用已成为感觉传导和疼痛中的重要界面，可能是疼痛性周围神经病潜在机制的一个因素。角质形成细胞表达受体和通道，使它们能够“感知”机械和热刺激，并通过释放信使分子将信号传递到表皮神经纤维。角质形成细胞分泌的生长因子和细胞因子也可能影响支配表皮的感觉神经元内的长期变化。相反，感觉神经元内含有的神经肽具有调节角质形成细胞的能力，包括它们的细胞因子和生长因子的产生和分泌。导致神经性疼痛的部分周围神经损伤与受损神经纤维的变性和邻近未受损纤维的功能改变有关。表皮神经支配改变对动态神经-角质形成细胞关系的影响尚不清楚。该R21建议的目的是确定表皮神经支配对角质形成细胞蛋白表达和功能的影响。具体目标1将解决神经损伤引起的神经支配变化将改变角质形成细胞蛋白质表达和功能的假设。表皮神经支配和神经损伤诱导的超敏反应将与涉及感觉转导的受体和通道以及已知使感觉神经元敏感的细胞因子的角质形成细胞表达相关。将基于角质形成细胞ATP释放的测量来评价表皮的功能变化。具体目标2将确定感觉神经元对器官型培养物中角质形成细胞的蛋白质表达和功能的影响，其中神经元输入将通过与感觉神经元共培养来引入。这些实验将解决的假设，选择的感觉神经元的子集将有不同的角质形成细胞的影响。生物化学方法将用于识别神经角质细胞信号传导的候选介质。神经损伤后动态神经-角质形成细胞关系的变化可能通过幸存的表皮神经纤维的敏化和感觉刺激的角质形成细胞转导的变化而促成神经病理性疼痛机制。因此，神经角质形成细胞的相互作用和神经损伤的调制代表了神经损伤的病理生物学后果的一个以前未探索的组成部分，和他们的理解可能会导致识别新的外周治疗神经性疼痛的目标。公共卫生关系：拟议的项目将分析两个重要结构之间的相互作用在感官信息的传输：感觉神经和皮肤的表皮。这些研究将确定与神经损伤相关的角质形成细胞变化的模式，这将为深入分析神经-角质形成细胞相互作用对疼痛的贡献提供基础。操纵这些相互作用可能能够提供外周限制的治疗策略。