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

基本信息

批准号：
8630921
负责人：
Gregory John Gerling
金额：
$ 40.61万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630921
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 Diphtheria Toxin Engineering Environmental Risk Factor Equation 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&apos 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 novel nutrition object shape public health relevance receptor relating to nervous system research study response social social attachment somatosensory ultraviolet irradiation

项目摘要

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）：触摸是喂养、社交和避免身体伤害等基本行为的组成部分。在哺乳动物中，触觉是由嵌入皮肤的感觉受体编码的。哺乳动物的皮肤结构和机械特性是动态的，会随着许多生理和外部条件而变化，包括营养、体重、衰老和暴露于环境因素，如紫外线照射。人们对这些生理变化如何改变触觉感受器的神经信号传导知之甚少。该应用的目的是阐明在正常生理目标器官变化期间控制触觉传入的发射特性的外周机制。该项目重点关注小鼠缓慢适应 I 型 (SAI) 传入神经，将其作为模型系统，为计算和实验研究提供无与伦比的可访问性。默克尔细胞与有髓鞘的皮肤传入神经接触，形成介导 SAI 反应的轻触受体。该项目与人类健康高度相关，因为 1) 皮肤中的 SAI 反应是人类高触觉敏锐度的基础，但人们对生理性皮肤重塑如何改变其信号传导知之甚少； 2）了解正常神经元重塑的机制可以确定治疗病理性或与年龄相关的触觉变化的目标。解剖学研究表明，小鼠正常毛发生长期间皮肤神经支配密度发生变化。该应用程序将解决关键的开放性问题：1）毛囊循环过程中控制神经支配变化的机制是什么，2）神经支配的变化是否会导致感觉信号的改变？中心假设是触觉传入的结构可塑性控制着正常皮肤重塑过程中触摸诱发的放电特性。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、定量形态测量、组织生物力学和新型小鼠模型，以及新型神经元动力学网络模型、微分方程和固体力学等计算工具。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) 识别驱动神经元重塑的靶细胞类型和候选分子线索。该项目在概念上具有创新性，因为它解决了基础神经生物学中的一个新问题，该问题对于触摸刺激的编码至关重要。技术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来回答这些基本问题。通过确定健康皮肤中控制触摸诱发信号可靠性的机制，这些研究将为确定这些机制在衰老和病理生理状态下如何失效奠定基础。