Mechanisms of mechanosensory transduction in Merkel cells

默克尔细胞的机械感觉转导机制

• 批准号: 8109253
• 负责人: Ellen A Lumpkin
• 金额: $ 34.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109253
• 关键词: Afferent Neurons; American; Amputation; Basal lamina; Biology; Brain; Calcium; Cell Adhesion Molecules; Cells; Cellular Mechanotransduction; Complex; Conflict (Psychology); Development; Diabetes Mellitus; Disease; Electrophysiology (science); Environment; Epidermis; Family member; Funding; Genes; Goals; HIV Infections; Health; Human; Hypersensitivity; Image; Impairment; In Vitro; Injury; Intervention; Ion Channel; Ion Channel Gating; Lead; Limb structure; Mammals; Mediating; Medical; Membrane; Merkel Cells; Molecular; Molecular Target; Mus; Neurites; Neurons; Oils; Pain; Pattern; Peripheral Nerves; Peripheral Nervous System Diseases; Physiological; Physiology; Protein Isoforms; Proteins; Public Health; Research; Role; Sensory; Shapes; Signal Transduction; Skin; Social Interaction; Stretching; System; Techniques; Testing; Texture; Touch sensation; allodynia; braille; cell type; cellular transduction; chemotherapy; chronic pain; extracellular; foot; in vivo; novel therapeutics; pain receptor; receptor; research study; response; sensory mechanism; somatosensory; therapeutic target

DESCRIPTION (provided by applicant): The long-term goal of this research is to discover the force-transduction molecules that initiate touch and pain in mammals. These senses are essential for social interactions and for avoiding harmful environments; however, in pathophysiological states, touch hypersensitivity contributes to allodynia and chronic pain. The objective of this application is to define sensory transduction mechanisms in Merkel cell-neurite complexes. These complexes are exquisitely sensitive touch receptors in the skin that encode shapes and textures, such as Braille-like patterns in humans. They are made up of epidermal Merkel cells and the terminals of somatosensory afferent neurons. This application focuses on mouse Merkel cell-neurite complex physiology because it is the mammalian touch receptor that is most amenable to in vitro and in vivo experiments. Although they are one of only four conserved cell types in the vertebrate epidermis, the role of Merkel cells in skin biology is still unknown. The central hypothesis of the proposed research is that epidermal Merkel cells are mechanosensitive cells that transduce force via ion channels. If true, the resulting electrical signals will be sent via sensory neurons to the brain to encode gentle touch. This hypothesis will be directly tested by combining physiological techniques (calcium imaging approaches and electrophysiology) to analyze force-activated signals in Merkel cells and molecular approaches to identify genes that encode mechanotransduction machinery. Simplified in vitro systems will be used to elucidate mechanotransduction molecules, and intact imaging will assess the touch-sensitivity of Merkel cells in vivo. The specific aims are to: 1. Determine whether force-activated ion channels mediate mechanotransduction in Merkel cells. 2. Evaluate the contribution of extracellular tethers to touch sensitivity in Merkel cells. 3. Identify ion-channel subunits required for mechanotransduction in Merkel cells. PUBLIC HEALTH RELEVANCE: The application aims to identify genes essential for mechanotransduction in touch and pain receptors in the skin. When mechanosensation is disrupted by peripheral nerve damage, which accompanies a vast number of diseases (diabetes), infections (HIV) and medical interventions (chemotherapy), injuries often lead to permanent impairment that can necessitate limb amputation. Moreover, touch hypersensitivity is a common feature of chronic pain, a devastating public health problem afflicting >50 million Americans. By identifying the molecules that initiate neuronal signals that are 1) impaired in peripheral neuropathy and 2) overly active in chronic pain, these studies may provide molecular targets for the development of new therapeutics for these pathophysiological conditions.

描述（由申请人提供）：本研究的长期目标是发现在哺乳动物中引发触觉和疼痛的力传导分子。这些感官对于社会互动和避免有害环境至关重要；然而，在病理生理状态下，触觉超敏反应会导致异常性疼痛和慢性疼痛。这个应用程序的目的是定义感觉转导机制在默克尔细胞-神经突复合体。这些复合物是皮肤中非常敏感的触觉感受器，可以对形状和纹理进行编码，比如人类的盲文模式。它们由表皮梅克尔细胞和体感觉传入神经元的末梢组成。该应用主要针对小鼠默克尔细胞-神经突复合体生理学，因为它是哺乳动物的触觉受体，最适合体外和体内实验。虽然它们是脊椎动物表皮中仅有的四种保守细胞类型之一，但默克尔细胞在皮肤生物学中的作用仍然未知。提出的研究的中心假设是表皮默克尔细胞是通过离子通道传导力的机械敏感细胞。如果这是真的，由此产生的电信号将通过感觉神经元发送到大脑，以编码温柔的触摸。这一假设将通过结合生理学技术（钙成像方法和电生理学）来分析默克尔细胞中的力激活信号和分子方法来识别编码机械转导机制的基因，从而直接得到验证。简化的体外系统将用于阐明机械转导分子，完整的成像将评估Merkel细胞在体内的触摸敏感性。具体目标是：1。确定力激活离子通道是否介导默克尔细胞的机械转导。2. 评估细胞外系索对默克尔细胞触觉敏感性的贡献。3. 鉴定默克尔细胞机械转导所需的离子通道亚基。公共卫生相关性：该应用程序旨在识别皮肤触觉和疼痛感受器机械转导所必需的基因。当机械感觉因周围神经损伤而中断时，周围神经损伤伴随着大量疾病（糖尿病）、感染（艾滋病毒）和医疗干预（化疗），损伤往往导致永久性损伤，可能需要截肢。此外，触觉过敏是慢性疼痛的一个共同特征，这是一个严重的公共健康问题，折磨着5000万美国人。通过识别激活神经信号的分子，这些分子在周围神经病变中受损，在慢性疼痛中过度活跃，这些研究可能为开发针对这些病理生理条件的新疗法提供分子靶点。