Mechanisms of mechanosensory transduction in Merkel cells

默克尔细胞的机械感觉转导机制

基本信息

批准号：
9276568
负责人：
Ellen A Lumpkin
金额：
$ 55.99万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276568
关键词：
ATP Receptors Action Potentials Address Afferent Neurons Amyloid beta-Protein Behavioral Assay Brain Calcium Cell membrane Cell physiology Cells Cellular Mechanotransduction Chemical Synapse Cleaved cell Collaborations Complement Complex Environment Epithelial Cells Glutamates Goals Hair Hand Human In Vitro Ion Channel Ions Knowledge Label Labyrinth Life Light Mechanics Mechanoreceptors Mediating Merkel Cells Modeling Molecular Movement Mus Nerve Nervous system structure Neuraxis Neurites Neuromodulator Neurons Neuropeptides Neurotransmitters Newborn Infant Paracrine Communication Pathway interactions Peripheral Physiology Process Protein Isoforms Proteins Reporter Research Role SNAP receptor Sensory Sensory Process Serotonin Shapes Signal Transduction Site Skin Stimulus Synapses Synaptic Transmission Synaptic Vesicles Tactile Testing Time Tissues Touch sensation Transgenic Mice VAMP-1 Vesicle Vibrissae Whole-Cell Recordings autocrine behavioral study cell type cellubrevin fluorescence imaging grasp imaging study in vivo innovation insight live cell imaging mechanical force monoamine neuroregulation neurotransmission neurotransmitter release optogenetics pressure presynaptic prevent public health relevance receptor response social attachment somatosensory tetanospasmin vesicular release virtual voltage

项目摘要

DESCRIPTION (provided by applicant): The sense of touch is vital for our survival, as it is essential for purposes as simple as picking up a fork and as complex as bonding with a newborn. Despite its importance for accomplishing basic tasks, the molecular and cellular mechanisms that convert a force on the skin into a neural signal are poorly understood. The long term goal of this research is to elucidate how receptors in the skin convert a touch stimulus into a neural signal to inform our brains about the physical world. We use Merkel cell-neurite complexes, which are conserved discriminative touch receptors, as a model to study these processes. Merkel cells are epithelial derived target cells that contact the endings of sensory neurons that send information to the central nervous system. Stimulating these Merkel cell-neurite complexes generates slowly adapting type I responses, which are important for detecting object features such as edges and curvature. Our previous studies revealed that Merkel cells directly sense mechanical force and convey this information to the underlying sensory neurons. The molecules that govern this process are completely unknown. Numerous molecules involved in synaptic transmission and neurotransmitters have been identified in Merkel cells, yet attempts to identify signaling mechanisms in vivo have yielded contradictory results. Thus, the objective of this research is to identify mechanisms by which Merkel cells convey tactile information to the nervous system. We will accomplish this goal by using an innovative combination of transgenic mice, optogenetics, in vitro and ex vivo physiology, and behavioral studies. Our central hypothesis is that Merkel cells release neurotransmitters at TeNT-sensitive SNARE-dependent chemical synapses to excite firing in tactile afferents. In Aim 1, we will determine whether Merkel cells employ TeNT-sensitive SNARE-mediated vesicular release. Aim 2 will identify the neurotransmitter or neuromodulatory pathways that excite Merkel-cell afferent neurons. These studies will yield fundamental insights into peripheral tactile mechanisms, which is essential to advance basic knowledge of principles that govern encoding of somatic senses.

描述（由申请人提供）：触觉对于我们的生存至关重要，因为它对于简单的（例如拿起叉子）和复杂的（例如与新生儿建立联系）至关重要，尽管它对于完成基本任务很重要，但分子和神经元的作用却至关重要。人们对将皮肤上的力转化为神经信号的细胞机制知之甚少，这项研究的长期目标是阐明皮肤中的受体如何将触摸刺激转化为神经信号，以告知我们的大脑关于物理世界的信息。使用默克尔细胞-神经突复合物，它们是保守的辨别性触摸受体，作为研究这些过程的模型，默克尔细胞是上皮衍生的靶细胞，接触感觉神经元的末端，刺激这些默克尔细胞-神经突复合物。产生缓慢适应的 I 型反应，这对于检测边缘和曲率等物体特征非常重要，默克尔细胞直接感知机械力并将此信息传递给底层的感觉神经元。在默克尔细胞中已经鉴定出许多参与突触传递和神经递质的分子，但鉴定体内信号传导机制的尝试却产生了矛盾的结果，因此，本研究的目的是确定默克尔细胞传递信号的机制。我们将通过使用转基因小鼠、光遗传学、体外和离体生理学以及行为研究的创新组合来实现这一目标。我们的中心假设是默克尔细胞在TeNT 敏感的 SNARE 依赖性化学突触刺激触觉传入神经的放电在目标 1 中，我们将确定 Merkel 细胞是否采用 TeNT 敏感的 SNARE 介导的囊泡释放，目标 2 将识别刺激 Merkel 细胞传入神经的神经递质或神经调节途径。这些研究将为外周触觉提供基本的见解。机制，这对于增进控制躯体感觉编码原理的基本知识至关重要。