Determinants of Mechanotransduction Sensitivity

力转导敏感性的决定因素

• 批准号: 8982095
• 负责人: Samata Katta
• 金额: $ 3.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982095
• 关键词: Affect; Afferent Neurons; Air; American Society of Hematology; Animals; Arachidonic Acids; Area; Bacteria; Behavior; Behavioral; Bicycling; Binding; Biological Models; Biomechanics; Blood Pressure; Caenorhabditis elegans; Cell membrane; Chemotherapy-induced peripheral neuropathy; Complex; Cytoskeleton; Diabetes Mellitus; Disease; Distress; Electrophysiology (science); Environment; Epithelial; Equilibrium; Esters; Etiology; Exhibits; Extracellular Matrix; Face; Family; Genetic; Goals; Hearing; Hyperalgesia; Hypersensitivity; In Vitro; Injury; Ion Channel; Kinetics; Link; Mammals; Measures; Mechanics; Mechanoreceptors; Membrane; Modality; Modeling; Molecular; Nematoda; Neurons; Nose; Numbness; Pain; Painless; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Photons; Polyunsaturated Fatty Acids; Property; Proteins; Quality of life; Research; Retinal; Risk; Role; Sensory; Signal Transduction; Smell Perception; Sodium Channel; Stimulus; Stress; Structure; Symptoms; Taste Perception; Techniques; Texture; Touch sensation; Translating; Variant; Vision; Work; allodynia; bird song; chemotherapy; diabetic; emergency service responder; epithelial Na+ channel; in vivo; insight; member; public health relevance; receptor; research study; response; somatosensory

 DESCRIPTION (provided by applicant): The sense of touch is vital for interacting with the world around us. Increases in sensitivity to touch, as in hyperalgesia or allodynia, and loss of sensation, as in diabetic or chemotherapy-induced peripheral neuropathy, can both diminish quality of life. Some of these changes in somatosensation may occur at the molecular level in the primary sensory neurons, yet how the first responders in touch detect a mechanical stimulus is still a mystery. We know neither how the initial ion channel opening occurs in mechanotransduction, nor how differences in the transfer of mechanical energy to and through the channel can affect the sensitivity of the neuron to touch. The overall goal of this proposal is to investigate how sensitivity to mechanical stimuli is affected by the structure of mechanotransduction channels and by the environment that surrounds them. Genetic and morphological variation among somatosensory neurons allows us to sense inputs ranging from a puff of air to a painful scrape. In C. elegans, different classes of mechanoreceptor neurons transduce mechanical stimuli with differing levels of sensitivity, making it a useful model system for studying mechanosensitivity. Working with this genetically tractable model allows us to investigate the properties of these channels within their natural environment. Previous work in our lab provides evidence that different channels expressed in distinct neurons exhibit different sensitivity to force. In preliminary studies, I found differences in constitutive currents between heterologously expressed wild-type MEC-4 channels and chimeric channels containing segments of the homologous DEG-1 channel. In the proposed research, I will use these chimeric channels to explore the role of various channel domains in determining the sensitivity of a given neuron within a specific environment. Other work from our lab has shown that the composition of the plasma membrane affects the ability of worms to sense touch. I will investigate the specific effects of these membrane manipulations on mechanotransduction. By increasing our understanding of the molecular mechanisms that underlie differences in mechanosensitivity, we may be better able to predict the molecular and cellular changes occurring in sensitization disorders and peripheral neuropathy.

 描述（由适用提供）：接触感对于与我们周围的世界互动至关重要。如糖尿病或化学疗法诱导的周围神经病一样，对触摸的敏感性增加，以及感觉丧失，都可以降低生活质量。节感上的某些变化可能发生在主要感觉神经元的分子水平上，但是触摸中的第一反应者如何检测机械刺激仍然是一个谜。我们不知道机械传导中的初始离子通道打开是如何发生的，也不知道机械能传递和通过通道的转移差异如何影响神经元对接触的敏感性。该提议的总体目标是 为了研究机械传输通道的结构以及周围环境的结构，对机械刺激的敏感性如何受到影响。体感神经元之间的遗传和形态变异使我们能够感知从空气到痛苦的刮擦的投入。在秀丽隐杆线虫中，具有不同敏感性水平的不同类别的机械刺激，使其成为研究机械敏感性的有用模型系统。使用这种一般可牵引的模型，我们可以研究这些渠道在其自然环境中的特性。我们实验室中的先前工作提供了证据，表明在不同的神经元中表达的不同通道暴露了对力的不同敏感性。在初步研究中，我发现异源表达的野生型MEC-4通道与包含同源DEG-1通道段的嵌合通道之间的本构电流差异。在拟议的研究中，我将使用这些嵌合通道来探讨各种通道域在确定特定环境中给定神经元的敏感性方面的作用。我们实验室的其他工作表明，质膜的组成会影响蠕虫感受触摸的能力。我将研究这些膜操作对机械转导的特定作用。通过提高我们对机理敏感性差异的分子机制的理解，我们可能会更好地预测敏感性障碍和周围神经病变中发生的分子和细胞变化。