Cellular and ion channel mechanisms underlying the sense of light touch in mammal

哺乳动物光触觉的细胞和离子通道机制

• 批准号: 8576721
• 负责人: JIANGUO GU
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576721
• 关键词: Action Potentials; Anesthesia procedures; Cell membrane; Cell physiology; Cells; Clinical; Complex; Data; Development; Diabetes Mellitus; Discrimination; Disease; Epidermis; Fiber; Fingers; Fire - disasters; Functional disorder; Gated Ion Channel; Goals; Hair follicle structure; Human; In Situ; Investigation; Ion Channel; Knowledge; Lead; Life; Light; Lip structure; Mammals; Measures; Mechanical Stimulation; Mechanics; Mediating; Membrane; Merkel Cells; Merkel cell carcinoma; Molecular; Neurites; Organ; Outcome; Pain; Patch-Clamp Techniques; Positioning Attribute; Property; Research; Science; Sensory; Shapes; Signal Transduction; Staging; Structure; Synapses; Tactile; Techniques; Testing; Texture; Time; Touch sensation; Transducers; Vibrissae; base; chemotherapy; innovation; mechanical allodynia; patch clamp; prevent; public health relevance; response; transmission process; vibration; voltage

DESCRIPTION (provided by applicant): The sense of light touch is critically important for daily life but this important sense can be altered to result in sensory dysfunctions such as tactile anesthesia and mechanical allodynia under pathological conditions. How mammals can sense light touch has been one of the biggest mysteries in science. This lack of knowledge prevents development of potentially effective approaches for preventing or treating mechanical sensory dysfunctions. Our long-term-goal is to uncover the cellular and molecular mechanisms underlying the sense of light touch in mammals. As the first stage of our long-term goal, the overall objective of this application is to study mechanisms underlying mechanical transduction of Merkel cell-neurite complex, a sensory structure essential for sensing light touch in mammals. Our central hypothesis is that Merkel cells are mechanical transducer cells that express mechanically activated ion channels (MA) and that activation of these channels triggers Merkel cells to fire action potentials and release excitatory transmitters. This hypothesis is based on ou preliminary results obtained by using our recently developed patch-clamp recordings from Merkel cells situated in whisker hair follicles (Merkel cell in situ patch-clamp technique). This innovative technique has, for the first time, led us to successfully record MA currents from Merkel cells. We have further discovered that Merkel cells in situ fire action potentials in response to mechanical stimulation. Our unique expertise of Merkel cell in situ patch-clamp recording technique places us at an advanced position to test the hypothesis with the following specific aims: 1) Elucidate ionic mechanisms of MA currents that excite Merkel cells in situ and characterize Merkel cell MA channel properties; 2) Identity ion channels that encode mechanical activity in Merkel cells; and 3) Delineate the mechanisms underlying the transmission of mechanical activity by Merkel cells. The outcomes of the above investigations will provide scientific knowledge about the sense of light touch at a cellular and molecular level. The study may have clinical implications ranging from sensory dysfunctions seen in diabetes and other disease conditions to Merkel cell malfunctions such as Merkel cell carcinoma.

描述（由申请人提供）：轻触感对于日常生活至关重要，但这种重要的感觉可能会被改变而导致感觉功能障碍，例如病理条件下的触觉麻醉和机械异常性疼痛。哺乳动物如何感知光触一直是科学上最大的谜团之一。这种知识的缺乏阻碍了预防或治疗机械感觉功能障碍的潜在有效方法的开发。我们的长期目标是揭示哺乳动物光触觉背后的细胞和分子机制。作为我们长期目标的第一阶段，该应用的总体目标是研究默克尔细胞神经突复合体机械转导的机制，默克尔细胞神经突复合体是哺乳动物感知光触所必需的感觉结构。我们的中心假设是，默克尔细胞是机械换能器细胞，表达机械激活的离子通道（MA），这些通道的激活会触发默克尔细胞激发动作电位并释放兴奋性递质。这一假设基于使用我们最近开发的胡须毛囊默克尔细胞膜片钳记录（默克尔细胞原位膜片钳技术）获得的初步结果。这项创新技术首次使我们成功记录了默克尔细胞的 MA 电流。我们进一步发现默克尔细胞响应机械刺激而产生原位激发动作电位。我们在默克尔细胞原位膜片钳记录技术方面的独特专业知识使我们处于领先地位，可以通过以下具体目标来检验假设：1）阐明原位激发默克尔细胞的MA电流的离子机制并表征默克尔细胞MA通道特性； 2）识别默克尔细胞中编码机械活动的离子通道； 3) 描述默克尔细胞机械活动传递的潜在机制。上述研究的结果将提供有关细胞和分子水平上的光触感的科学知识。这项研究可能具有临床意义，从糖尿病和其他疾病中出现的感觉功能障碍到默克尔细胞功能障碍（例如默克尔细胞癌）。