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The role of Atoh1 in the development and function of Merkel cells

Atoh1在默克尔细胞发育和功能中的作用

基本信息

批准号：
8490166
负责人：
STEPHEN M MARICICH
金额：
$ 30.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2010-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490166
关键词：
Adult Affect Area BHLH Protein Behavior Behavioral Brain Cell Maintenance Cell physiology Cells Characteristics Complex Cutaneous Denervation Dermal Detection Development Developmental Process Discrimination Disease Ectopic Expression Epidermis Fiber Genes Genetic Goals Histological Techniques Human In Vitro Inherited Injury Knock-out Laboratories Life Maintenance Malignant Neoplasms Mammals Mechanics Mechanoreceptors Mediating Merkel Cells Merkel cell carcinoma Molecular Mus Natural regeneration Nerve Nerve Fibers Nervous system structure Neurites Pathway interactions Pattern Perception Peripheral Nerves Peripheral Nervous System Play Population Positioning Attribute Production Psychophysics Research Role Sensory Shapes Signal Transduction Skin Skin Neoplasms Stimulus System Testing Texture Touch sensation Vibrissae Work afferent nerve behavior test cell type density design foot human disease in vivo injured insight mature animal nervous system disorder neurophysiology programs public health relevance receptor research study response somatosensory transcription factor

项目摘要

DESCRIPTION (provided by applicant): Disruptions of the sense of touch are inherent to many inherited and acquired human disorders that affect the skin and/or peripheral nervous system. These disorders can affect some or all of the touch receptors that are found in the skin. Merkel cell/neurite complexes are one form of cutaneous touch receptor, and they are composed of sensory nerve fibers and skin cells called Merkel cells. Merkel cell/neurite complexes are thought to be important for two-point touch discrimination and the perception of curvature, shapes and textures. Atoh1 is a basic helix-loop-helix transcription factor expressed by Merkel cells that is necessary for their production. In turn, Merkel cells are essential for the detection of touch stimuli detected by Merkel cell/neurite complexes. The developmental processes that control the genesis and assembly of Merkel cell/neurite complexes, the ongoing requirement for Atoh1 in Merkel cells, and the role(s) that these cells play in human diseases of the peripheral nervous system and skin, including Merkel cell carcinoma, remain unknown. Our goals are to understand how Merkel cells function in sensory perception and to identify the genetic factors that control Merkel cell development. The specific aims of this proposal are to 1) determine the consequences of Merkel cell deletion on mouse behavior; 2) determine whether Atoh1 is sufficient to direct the production of Merkel cells; and to 3) determine how conditional loss of Atoh1 in adult animals affects Merkel cells and Merkel cell/neurite complexes. We will use conditional knockout systems to delete Atoh1 from the skin of developing mice and then use specialized behavioral tests to assess the sensory functions proposed to be mediated by Merkel cell/neurite complexes. We will also use histological techniques to determine the affects of Atoh1 deletion on adult Merkel cells and how this deletion impacts the ability of damaged nerves to regenerate and accurately target Merkel cell/neurite complexes. Finally, we will ectopically express Atoh1 in different regions of adult skin to determine whether the gene is sufficient to direct the creation of new Merkel cells and/or Merkel cell carcinomas.

描述（由申请人提供）：触觉中断是许多遗传性和获得性人类疾病所固有的，这些疾病会影响皮肤和/或周围神经系统。这些疾病会影响皮肤中的部分或全部触觉感受器。默克尔细胞/神经突复合物是皮肤触觉感受器的一种形式，它们由感觉神经纤维和被称为默克尔细胞的皮肤细胞组成。默克尔细胞/神经突复合体被认为对两点触摸辨别和对曲率、形状和纹理的感知很重要。Atoh1是默克尔细胞表达的一种基本的螺旋-环-螺旋转录因子，是其产生所必需的。反过来，默克尔细胞对于默克尔细胞/神经突复合体检测到的触摸刺激的检测至关重要。控制默克尔细胞/神经突复合物的发生和组装的发育过程，默克尔细胞对Atoh1的持续需求，以及这些细胞在人类周围神经系统和皮肤疾病（包括默克尔细胞癌）中所起的作用仍不清楚。我们的目标是了解默克尔细胞在感官知觉中的功能，并确定控制默克尔细胞发育的遗传因素。该提案的具体目的是：1)确定默克尔细胞缺失对小鼠行为的影响；2)确定Atoh1是否足以指导默克尔细胞的产生；3)确定成年动物Atoh1的条件性丧失如何影响默克尔细胞和默克尔细胞/神经突复合物。我们将使用条件敲除系统从发育中的小鼠皮肤中删除Atoh1，然后使用专门的行为测试来评估由默克尔细胞/神经突复合物介导的感觉功能。我们还将使用组织学技术来确定Atoh1缺失对成年默克尔细胞的影响，以及这种缺失如何影响受损神经的再生能力，并准确地靶向默克尔细胞/神经突复合物。最后，我们将在成人皮肤的不同区域异位表达Atoh1，以确定该基因是否足以指导新的默克尔细胞和/或默克尔细胞癌的产生。