Identification of proteins that structurally couple epidermal cells to somatosensory neurons

摘要 表皮细胞为感觉刺激提供第一接触点，并受躯体感觉神经元支配 （SSN）塑造了我们对世界的体验。SSN和表皮细胞都具有重要的临床意义; SSN是生理性和病理性疼痛的介质，并且一些病理性皮肤状况与之相关。 伴随着虚弱的疼痛和瘙痒然而，我们对表皮细胞在SSN发育中所起作用的理解， 和功能，特别是伤害感受，除了几个充分研究的例子之外，仍然是有限的。表征 这些重要的细胞间相互作用由于脊椎动物的异质性和复杂性而变得复杂。 神经系统在这里，我们建议使用一个综合的跨物种的方法来确定分子介质 一种进化上保守的细胞内相互作用，包括表皮细胞包裹SSN神经突， 细胞这种细胞间相互作用的保守性和伤害感受器的优先鞘化 与其他SSN相比，这些鞘可能在发育和功能中发挥关键作用。 伤害性SSN。首先，我们将利用果蝇神经遗传学的优势标记表皮鞘- 相关的蛋白质，用于通过质谱鉴定和体内下游功能分析。第二、 我们将扩展我们对无脊椎动物和脊椎动物表皮鞘的比较分析，结合 斑马鱼的功能研究和跨物种拯救研究，以确定一个中心的保守功能， 鞘成熟的调节因子。该项目的成功完成将提供深入了解分子 在解剖学上将表皮细胞与伤害感受器结合并有助于伤害感受器发育的机制 和功能鉴于病理性疼痛对生活质量的巨大影响-慢性疼痛影响的不仅仅是 三分之一的美国人-了解表皮细胞如何调节伤害感受SSN功能是非常重要的 对开发新疼痛治疗药物感兴趣。

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.