Identification of proteins that structurally couple epidermal cells to somatosensory neurons

摘要 表皮细胞是感觉刺激的第一个接触点，由体感神经元支配。 (SSN)塑造了我们对世界的体验。SSN和表皮细胞均具有重要的临床意义； SSN是生理性和病理性疼痛的媒介，与某些病理性皮肤状况有关 伴随着衰弱的疼痛和瘙痒。然而，我们对表皮细胞在SSN发育中所起作用的理解 而功能，特别是伤害性感受，除了几个研究得很好的例子外，仍然有限。刻画 脊椎动物的异质性和复杂性使这些重要的细胞间相互作用变得复杂 神经系统。在这里，我们建议使用跨物种的综合方法来识别分子介体。 一种进化保守的细胞内相互作用，涉及到表皮包裹SSN神经突起 细胞。这种细胞间相互作用的保守性和伤害性感受器的优先包膜 与其他SSN的比较表明，这些鞘可能在卵巢的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来标记表皮鞘-- 相关蛋白用于体内质谱学和下游功能分析鉴定。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救援研究以确定中枢的保守功能 鞘成熟的调节剂。这个项目的成功完成将提供对分子的洞察 将表皮细胞解剖地连接到伤害性感受器并促进伤害性感受器发育的机械 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性SSN功能非常重要 对疼痛管理新疗法的开发感兴趣。

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.