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（由申请人提供）：触觉对于我们与周围世界的互动至关重要。触觉敏感性的增加（如痛觉过敏或异常性疼痛）和感觉丧失（如糖尿病或化疗引起的周围神经病变）都可能导致这种情况。身体感觉的一些变化可能发生在初级感觉神经元的分子水平上，但触摸中的第一反应者如何检测机械刺激仍然是一个谜，我们也不知道最初的离子通道是如何的。开放发生在机械传导中，以及机械能传输到和通过通道的差异如何影响神经对触摸的敏感性。该提案的总体目标是。 研究线虫对机械刺激的敏感性如何受到机械传导通道结构及其周围环境的影响。体感神经元之间的遗传和形态变异使我们能够感知从一阵空气到痛苦的刮擦等各种输入。 ，不同类别的机械感受器神经元以不同的敏感性水平传导机械刺激，使其成为研究机械敏感性的有用模型系统，使用这种遗传易处理的模型使我们能够研究机械敏感性。我们实验室之前的工作提供了证据，表明不同神经元中表达的不同通道对力表现出不同的敏感性，在初步研究中，我发现异源表达的野生型 MEC-4 通道和 MEC-4 通道之间的本构电流存在差异。包含同源 DEG-1 通道片段的嵌合通道 在拟议的研究中，我将使用这些嵌合通道来探索各种通道域在确定特定环境中给定神经元的敏感性中的作用。表明其组成为质膜影响蠕虫感知触觉的能力，我将研究这些膜操作对机械传导的具体影响，通过增加我们对机械敏感性差异的分子机制的理解，我们可能能够更好地预测分子和细胞。敏化障碍和周围神经病变中发生的变化。