Peripheral Mechanisms Governing Tactile Encoding During Normal Target Remodeling

正常目标重塑期间控制触觉编码的外围机制

• 批准号: 9115728
• 负责人: Gregory John Gerling
• 金额: $ 37.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115728
• 关键词: Ablation; Address; Aging; Apoptosis; Architecture; BMP4; Behavior; Biocompatible Materials; Biological Models; Biology; Biomechanics; Body Weight; Brain; Cells; Code; Complex; Computer Simulation; Cues; Cutaneous; Deoxyuridine; Differential Equation; Diphtheria Toxin; Engineering; Environmental Risk Factor; Exposure to; Face; Goals; Growth; Hair; Hair follicle structure; Health; Human; Label; Lead; Mammals; Mechanics; Mediating; Merkel Cells; Modeling; Molecular; Mus; NTF3 gene; Neurites; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences; Organ; Organogenesis; Peripheral; Phase; Physiological; Property; Quantitative Microscopy; Ranvier' s Nodes; Research; Rest; Sensory; Sensory Receptors; Shapes; Signal Transduction; Skin; Solid; Specific qualifier value; Staging; Stimulus; Structure; System; Tactile; Techniques; Testing; Texture; Thick; Tissues; Touch sensation; Transgenic Mice; age related; cell type; computer studies; computerized tools; density; feeding; in vivo; innovation; interdisciplinary approach; morphometry; mouse model; nerve supply; network models; neurophysiology; neurotransmission; novel; nutrition; object shape; receptor; research study; response; social; social attachment; somatosensory; ultraviolet irradiation; Ablation; Address; Aging; Apoptosis; Architecture; BMP4; Behavior; Biocompatible Materials; Biological Models; Biology; Biomechanics; Body Weight; Brain; Cells; Code; Complex; Computer Simulation; Cues; Cutaneous; Deoxyuridine; Differential Equation; Diphtheria Toxin; Engineering; Environmental Risk Factor; Exposure to; Face; Goals; Growth; Hair; Hair follicle structure; Health; Human; Label; Lead; Mammals; Mechanics; Mediating; Merkel Cells; Modeling; Molecular; Mus; NTF3 gene; Neurites; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences; Organ; Organogenesis; Peripheral; Phase; Physiological; Property; Quantitative Microscopy; Ranvier' s Nodes; Research; Rest; Sensory; Sensory Receptors; Shapes; Signal Transduction; Skin; Solid; Specific qualifier value; Staging; Stimulus; Structure; System; Tactile; Techniques; Testing; Texture; Thick; Tissues; Touch sensation; Transgenic Mice; age related; cell type; computer studies; computerized tools; density; feeding; in vivo; innovation; interdisciplinary approach; morphometry; mouse model; nerve supply; network models; neurophysiology; neurotransmission; novel; nutrition; object shape; receptor; research study; response; social; social attachment; somatosensory; ultraviolet irradiation

DESCRIPTION (provided by applicant): Touch is integral to essential behaviors such as feeding, social bonding and avoiding bodily harm. In mammals, touch is encoded by sensory receptors embedded in the skin. Mammalian skin structure and mechanical properties are dynamic, changing in response to numerous physiological and external conditions, including nutrition, body weight, aging and exposure to environmental factors, such as UV irradiation. Little is known about how these physiologic changes alter neuronal signaling from touch receptors. The objective of this application is to elucidate peripheral mechanisms that govern the firing properties of tactile afferents during normal physiological target-organ changes. The project focuses on mouse slowly adapting type I (SAI) afferents as a model system with unparalleled accessibility for computational and experimental studies. Merkel cells in contact with myelinated cutaneous afferents form gentle-touch receptors that mediate SAI responses. This project is highly relevant to human health because 1) SAI responses in the skin underlie high tactile acuity in humans but little is known about how physiological skin remodeling alters their signaling; and 2) understanding mechanisms of normal neuronal remodeling could identify targets for treating pathological or age-related changes in touch sensitivity. Anatomical studies have shown that skin innervation density changes during normal hair growth in mice. This application will address key open questions: 1) what are the mechanisms that govern innervation changes during hair-follicle cycling, and 2) do changes in innervation lead to altered sensory signaling? The central hypothesis is that structural plasticity of tactile afferents govern touch-evoked firing properties during normal skin remodeling. The hypothesis will be tested with an innovative multidisciplinary approach combining experimental techniques, including neurophysiology, 3D microscopy, quantitative morphometry, tissue biomechanics and novel mouse models, with computational tools such as novel network models of neuronal dynamics, differential equations and solid mechanics. Aims are to 1) define temporal dynamics and cellular mechanisms of neuronal remodeling during skin renewal, 2) analyze the functional consequences of neuronal remodeling on mechanical encoding, and 3) identify the target cell type and candidate molecular cues that drive neuronal remodeling. This project is conceptually innovative because it tackles a novel question in basic neurobiology that is central to the encoding of touch stimuli. Technically innovation lies in its unique, interdisciplinary approaches to combine experimental biology with computational studies to answer these fundamental questions. By identifying mechanisms that govern the reliability of touch-evoked signals in healthy skin, these studies will set the stage to determine how these mechanisms fail in aging and pathophysiological states.

描述（由申请人提供）：触摸是诸如喂养，社会联系和避免身体伤害之类的基本行为不可或缺的。在哺乳动物中，触摸是由嵌入皮肤中的感觉受体编码的。哺乳动物的皮肤结构和机械性能是动态的，响应着许多生理和外部条件，包括营养，体重，衰老和暴露于环境因素，例如紫外线照射。关于这些生理变化如何改变触摸受体的神经元信号传导知之甚少。该应用的目的是阐明在正常生理目标和器官变化过程中控制触觉传入的发射特性的外围机制。该项目着重于小鼠缓慢适应I型（SAI）传入作为模型系统，具有无与伦比的计算和实验研究。与髓鞘皮肤传入的默克尔细胞形成介导SAI反应的柔和接触受体。该项目与人类健康高度相关，因为1）皮肤中的SAI反应是人类高触觉的基础，但对生理皮肤改造的方式鲜为人知。 2）理解正常神经元重塑的机制可以鉴定出治疗病理学或年龄相关的触摸敏感性变化的靶标。 解剖学研究表明，在小鼠正常头发生长过程中，皮肤支配密度变化。该应用程序将解决关键的开放问题：1）在毛囊循环过程中支配神经变化的机制是什么，而2）神经支配的变化是否导致感觉信号改变？中心假设是触觉传入的结构可塑性控制着正常皮肤重塑期间接触式诱发的射击特性。该假设将通过创新的多学科方法进行测试，该方法结合了实验技术，包括神经生理学，3D显微镜，定量形态计量学，组织生物力学和新型小鼠模型，以及计算工具，例如新型神经元动力学网络模型，微分方程和固体机制。目的是1）定义皮肤更新过程中神经元重塑的时间动力学和细胞机制，2）分析神经元重塑对机械编码的功能后果，3）确定靶细胞类型和候选分子提示，这些分子提示驱动神经元重塑。该项目在概念上是创新的，因为它解决了基本神经生物学中的一个新问题，这对于触摸刺激的编码至关重要。从技术上讲，创新在于其独特的跨学科方法，将实验生物学与计算研究相结合以回答这些基本问题。通过确定控制健康皮肤中接触诱发信号的可靠性的机制，这些研究将奠定阶段，以确定这些机制如何在衰老和病理生理状态下失败。