New approaches to identify molecular mechanisms of touch and pain in mammals

描述(由申请人提供) 摘要：机械传递是机械能转化为电信号或生化信号的过程。在哺乳动物中，机械转导是多种感官的基础，包括听觉、触觉和本体感觉。基本的生理过程，如血压调节和膀胱功能，也依赖于机械转导来实现正常的内稳态功能。尽管它具有广泛的重要性，但人们对哺乳动物机械转导的分子机制知之甚少。不同的细胞是否使用相同的转导分子，这些分子被细胞环境所改变？或者，是否有多个机械传感器专门用于感知不同类型的机械刺激？他的提议的目标是识别在哺乳动物体感神经元中介导机械转导的分子，这些细胞传递我们的触觉和疼痛。虽然已经确定了一些候选的机械转导分子，但这些候选分子的异源表达并没有产生功能上的机械敏感通道，也没有基因敲除研究证实这些候选分子中的任何一个在哺乳动物的体感机械转导中发挥作用。我的实验室将采取几种无偏见的方法来识别新的候选机械转导分子。这项提议的具体目的是：(1)确定机械转导机制的组件；(2)检查候选分子对体内躯体感觉的贡献。这些研究将为哺乳动物机械转导背后的分子力传感器提供新的见解。 与公共卫生相关：虽然疼痛令人不快，但它警告我们注意环境中的有害刺激，并唤起保护性反射。但疼痛也可能是一种慢性的、令人衰弱的痛苦，不再起到保护作用。慢性疼痛不仅发生在创伤引起的炎症和组织损伤之后，也是许多疾病的结果；疼痛是癌症、艾滋病和糖尿病患者的主要主诉。了解引起急性和慢性疼痛的机制可能会导致开发出急需的新药和疗法来缓解疼痛。

DESCRIPTION (Provided by the applicant) Abstract: Mechanotransduction is the process by which mechanical energy is converted into electrical or biochemical signals. In mammals, mechanotransduction underlies a variety of senses, including hearing, touch and proprioception. Basic physiological processes, such as blood-pressure regulation and bladder function, also rely on mechanotransduction for normal homeostatic function. Despite its widespread importance, little is known about the molecular mechanisms underlying mechanotransduction in mammals. Do different cells use the same transduction molecules that are modified by cellular context? Or, are there multiple mechanotransducers that specialize in sensing different types of mechanical stimuli? The goal of his proposal is to identify molecules that mediate mechanotransduction in mammalian somatosensory neurons, the cells that convey our sense of touch and pain. While some candidate mechanotransducers have been identified, heterologous expression of these candidates has not yielded functional mechanosensitive channels, nor have gene knockout studies confirmed a role for any of these candidates in mammalian somatosensory mechanotransduction. My laboratory will undertake several unbiased approaches to identify new candidate mechanotransduction molecules. The specific aims of this proposal are to: (1) Identify components of the mechanotransduction machinery and (2) Examine the contribution of candidate molecules to somatosensation in vivo. These studies will provide novel insight into the molecular force transducers that underlie mammalian mechanotransduction. Public Health Relevance: Though unpleasant, pain warns us against harmful stimuli in the environment and evokes protective reflexes. But pain can also be a chronic, debilitating affliction that no longer serves a protective purpose. Chronic pain not only occurs after trauma-induced inflammation and tissue injury, but also results from many diseases; pain is the major complaint of patients suffering from cancer, AIDS, and diabetes. Understanding the mechanisms that evoke acute and chronic pain may lead to the development of much needed, new drugs and therapies to alleviate pain.