Mechanisms of mechanosensory transduction in Merkel cells

默克尔细胞的机械感觉转导机制

基本信息

批准号：
7870306
负责人：
Ellen A Lumpkin
金额：
$ 35.86万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/7870306
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 Figs - dietary Funding Genes Goals HIV Infections 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 public health relevance receptor research study response sensory mechanism somatosensory therapeutic target

项目摘要

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）：这项研究的长期目标是发现启动哺乳动物触摸和疼痛的力 - 转移分子。这些感觉对于社交互动和避免有害环境至关重要。然而，在病理生理状态下，触摸过敏有助于异常疼痛和慢性疼痛。该应用的目的是定义默克尔细胞神经突配合物中的感觉转导机制。这些复合物是皮肤中精确敏感的触摸受体，它们编码形状和纹理，例如人类中的盲文样式。它们由表皮默克尔细胞和体感传入神经元的末端组成。该应用集中在小鼠默克尔细胞神经突复合物生理上，因为它是最适合体外和体内实验的哺乳动物触摸受体。尽管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。所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递力的机械敏感细胞。如果是正确的话，将通过感觉神经元发送到大脑以编码温和的触摸。该假设将通过结合生理技术（钙成像方法和电生理学）来直接检验，以分析默克尔细胞中的力激活信号和分子方法，以识别编码机械传导机械的基因。简化的体外系统将用于阐明机械传导分子，完整成像将评估体内默克尔细胞的接触敏感性。具体目的是：1。确定力激活的离子通道是否介导默克尔细胞中的机械转导。 2。评估细胞外系因接触默克尔细胞敏感性的贡献。 3。确定默克尔细胞机械转移所需的离子通道亚基。公共卫生相关性：该应用程序旨在确定皮肤中触摸和疼痛受体机械转导至关重要的基因。当机械敏度被周围神经损伤破坏时，伴随大量疾病（糖尿病），感染（HIV）和医疗干预措施（化学疗法），损伤通常会导致永久性损害，因此需要肢体截肢。此外，触摸超敏反应是慢性疼痛的共同特征，这是一个毁灭性的公共卫生问题，遭受了5000万美国人的困扰。通过鉴定启动神经元信号的分子1）在周围神经病中受损和2）在慢性疼痛中过度活跃，这些研究可能为这些病理生理状况的新疗法提供了分子靶标。