Mechanisms of force sensing in the nervous system

神经系统中的力传感机制

• 批准号: 10524765
• 负责人: Ardem Patapoutian
• 金额: $ 67.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524765
• 关键词: Cations; Functional disorder; Genomic approach; Hearing; Interoception; Ion Channel; Lung; Mechanics; Mediating; Molecular; Nervous System; Organ; Pain; Physiological; Physiology; Piezo 1 ion channel; Piezo 2 ion channel; Play; Process; Proprioception; Role; Satiation; Sensory; Smell Perception; Stretching; System; Taste Perception; Touch sensation; Vision; functional genomics; high throughput screening; mechanical force; mechanical stimulus; mechanotransduction; pain perception; receptor; sensor; sensory system; therapeutic target

Unlike sight, taste and smell, mechanical senses extend beyond a single sensory organ, and encompass processes as diverse as hearing, somatosensation, and interoception. Despite their physiological importance, the molecular identity of mechanotransduction channels is largely unknown. Our lab discovered the first vertebrate mechanically-gated cation channels, Piezo1 and Piezo2, and have shown that Piezo2 plays a critical role in detecting touch, proprioception and lung stretch, but not noxious mechanical stimuli. However, big questions remain: what other mechanosensory systems depend on Piezos, and what is the identity of the remaining noxious mechanosensors? We will explore the role of Piezo2 in various forms of internal-organ mechanotransduction (interoception), including satiety and baroreception - processes crucial for normal physiology and pathophysiology. Beyond Piezo2, unknown mechanosensors mediate the transduction of noxious mechanical forces leading to the perception of pain, and are anticipated to be important therapeutic targets. We will use high-throughput screens and functional genomics approaches to find these receptors. Identifying these elusive sensors will break open the pain field, as Piezo2 has done for touch.

与视觉、味觉和嗅觉不同，机械感觉超越了单一的感觉器官，涵盖了听觉、躯体感觉和内感受等多种过程。尽管其生理学重要性，但机械转导通道的分子特性在很大程度上是未知的。我们的实验室发现了第一个脊椎动物机械门控阳离子通道 Piezo1 和 Piezo2，并表明 Piezo2 在检测触觉、本体感觉和肺部伸展方面发挥着关键作用，但在检测有害机械刺激方面则不然。然而，仍然存在一些大问题：还有哪些机械感觉系统依赖于压电，以及剩余的有害机械传感器的身份是什么？我们将探讨 Piezo2 在各种形式的内脏机械力转导（内感受）中的作用，包括饱腹感和压力感受 - 对于正常生理学和病理生理学至关重要的过程。除了 Piezo2 之外，未知的机械传感器还介导有害机械力的传导，导致疼痛感知，预计将成为重要的治疗靶点。我们将使用高通量筛选和功能基因组学方法来寻找这些受体。识别这些难以捉摸的传感器将打破疼痛领域，就像 Piezo2 对触摸所做的那样。