Identification of proteins that structurally couple epidermal cells to somatosensory neurons

表皮细胞与体感神经元结构耦合的蛋白质的鉴定

基本信息

批准号：
10390199
负责人：
JAY Z PARRISH
金额：
$ 44.15万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390199
关键词：
Affect Age American Anatomy Biological Assay Biology Biotin Biotinylation C Fiber Cell Shape Cell membrane Cells Complex Couples Cutaneous Development Discrimination Drosophila Proteins Drosophila genus Drug Targeting Epidermis Erythrocytes Etiology Exhibits Fishes Free Nerve Ending Frequencies Genetic Goals Heterogeneity Image Individual Inflammation Mediators Intractable Pain Invertebrates Knowledge Label Ligase Link Liquid Chromatography Mass Spectrum Analysis Mechanical Stress Mechanoreceptors Mediating Mediator of activation protein Merkel Cells Modeling Molecular Morphogenesis Movement Nervous system structure Neurites Neurons Nociception Nociceptive Stimulus Nociceptors Opioid Receptor Optics Pacinian Corpuscles Pain Pain management Pathologic Perception Physiological Play Population Prevalence Proteins Proteomics Pruritus Public Health Quality of life Radial Research Role Schwann Cells Sensory Shapes Signal Transduction Skin Stimulus Structure Synapses System Therapeutic Touch sensation Zebrafish base chronic pain clinically relevant comparative experience fly genomic locus in vivo insight interest keratinocyte knock-down loss of function neurogenetics neuron development novel novel therapeutics pain perception pressure protein function receptor reconstitution response sensor sensory stimulus side effect somatosensory tool

项目摘要

ABSTRACT Epidermal cells provide the first point of contact for sensory stimuli and are innervated by somatosensory neurons (SSNs) that shape our experience of the world. Both SSNs and epidermal cells are of great clinical relevance; SSNs are mediators of physiological and pathological pain, and some pathological skin conditions are associated with debilitating pain and itch. However, our understanding of roles that epidermal cells play in SSN development and function, particularly nociception, remain limited aside from a few well-studied examples. Characterizing these important intercellular interactions is complicated by the heterogeneity and complexity of vertebrate nervous systems. Here, we propose to use an integrated cross-species approach to identify molecular mediators of an evolutionarily conserved intracellular interaction that involves the wrapping of SSN neurites by epidermal cells. The conservation of this intercellular interaction and the preferential ensheathment of nociceptors compared to other SSNs suggest that these sheaths may play key roles in development and function of nociceptive SSNs. First, we will exploit the advantages of Drosophila neurogenetics to label epidermal sheath- associated proteins for identification by mass-spectroscopy and downstream functional analysis in vivo. Second, we will extend our comparative analysis of invertebrate and vertebrate epidermal sheaths, combining loss-of- function studies in zebrafish and cross-species rescue studies to define conserved functions of a central regulator of sheath maturation. Successful completion of this project will provide insight into the molecular machinery that anatomically couples epidermal cells to nociceptors and contributes to nociceptor development and function. Given the enormous impact of pathological pain on quality of life – chronic pain affects more than one in three Americans – understanding how epidermal cells modulate nociceptive SSN function is of great interest for development of novel therapeutics for pain management.

抽象的表皮细胞提供了感官刺激的第一接触点，并由体感神经元支配（SSN）塑造了我们对世界的经验。 SSN和表皮细胞都具有很大的临床相关性。 SSN是身体和病理疼痛的介体，某些病理皮肤状况与疼痛和瘙痒。但是，我们对表皮细胞在SSN发育中起发挥作用的作用的理解除了一些经过精心研究的例子外，功能，尤其是伤害感受。特征这些重要的细胞间相互作用因脊椎动物的异质性和复杂性而变得复杂神经系统。在这里，我们建议使用集成的跨物种方法来识别分子介体进化的细胞内相互作用，涉及表皮包裹SSN神经细胞。这种相互作用的相互作用和伤害感受器的首选包裹的保护与其他SSN相比，这些鞘可能在开发和功能中起关键作用伤害性SSN。首先，我们将利用果蝇神经遗传学的优势来标记表皮鞘相关的蛋白质，用于通过体内质谱和下游功能分析鉴定。第二，我们将扩展对无脊椎动物和脊椎动物表皮鞘的比较分析，结合了损失斑马鱼和跨物种救援研究中的功能研究，以定义中央的配置功能鞘成熟的调节剂。该项目的成功完成将提供对分子的见解解剖学上表皮细胞与伤害感受器并有助于伤害感受器发育的机械和功能。鉴于病理痛苦对生活质量的巨大影响 - 慢性疼痛影响超过三分之一的美国人 - 了解表皮细胞如何调节伤害性SSN功能很棒兴趣开发用于疼痛管理的新疗法。