Molecular mechanism of neuronal control in sweat gland development

项目摘要 外分泌汗腺是人体皮肤中最丰富的腺体，对体温调节和 水平衡严重烧伤和先天性汗腺缺陷的患者不能正确地 保持体温，这可能导致中暑和器官衰竭。最近确定的 汗腺中的多能干细胞具有帮助这些人有效调节体温的巨大潜力 通过开辟新的汗腺再生的途径。尽管如此，功能齐全的汗液的再生 腺体将需要更好地了解内源性信号，通常调节汗液的分化， 腺干细胞精确的神经支配和神经元控制是汗液兴奋功能不可缺少的， 神经元信号引起出汗，而且，正如我们以前在实验室发现的那样，这些信号对于 汗腺成熟汗腺和神经元相互依赖，以实现精确的共同发展。然而，在这方面， 关于神经元输入如何影响汗腺发育，尤其是汗腺干的发育，目前还知之甚少 细胞我们假设神经元信号对于汗腺干细胞的特化是至关重要的 在发展过程中。以小鼠汗腺为模型，我们将研究汗液中的分子变化 腺干细胞在发育过程中缺乏神经支配，并进一步确定下游通路 在汗腺干细胞内，介导神经递质对干细胞维持的影响。通过 小鼠遗传学、免疫荧光共聚焦和光片成像、单细胞RNA 测序，荧光激活细胞分选，组织外植体和细胞培养系统，我们计划：1） 探讨去神经支配对汗腺发育和稳态的影响; 2）剖析 汗腺导管和汗腺发育中的特定神经递质;以及3）了解机制 钙通过其介导汗腺干细胞命运的神经元控制。完成我们建议的研究 将为神经系统影响汗腺的分子机制提供新的见解 不同发育阶段的形态发生和细胞命运决定。此外，我们的研究结果将提供 突破性地洞察了汗腺和神经如何共同发展成为一个功能单位，这反过来又会 促进对患有出汗不足的患者的再生疗法。

PROJECT SUMMARY Eccrine sweat glands are the most abundant glands in human skin and are essential for thermoregulation and water balance. Patients with severe burn injuries and congenital sweat gland deficiencies cannot properly maintain body temperature, which can lead to heat stroke and organ failure. The recent identification of multipotent stem cells in sweat glands presents great potential to help these people to thermoregulate efficiently by opening the way for de novo sweat gland regeneration. Nonetheless, regeneration of fully functional sweat glands will require better understanding of the endogenous signals that normally regulate differentiation of sweat gland stem cells. Precise innervation and neuronal control are indispensable for sweat glad function since neuronal signals elicit sweating, and further, as we previously discovered in our lab, these signals are critical for sweat gland maturation. Sweat glands and neurons rely on each other for precise co-development. However, very little is known about how neuronal inputs influence sweat gland development, especially sweat gland stem cells. We hypothesize that neuronal signals are critical for the specification of sweat gland stem cells during development. Using mouse sweat glands as a model, we will investigate the molecular changes in sweat gland stem cells during development when lacking innervation, and further identify the downstream pathway within sweat gland stem cells that mediate the effect of neurotransmitters upon stem cell maintenance. Through combined use of mouse genetics, immunofluorescent confocal and light sheet imaging, single-cell RNA sequencing, fluorescence-activated cell sorting, and tissue explant and cell culture systems, we plan to: 1) investigate the effect of denervation during sweat gland development and homeostasis; 2) dissect the roles of specific neurotransmitters in sweat ducts and sweat gland development; and 3) understand the mechanism(s) by which calcium mediates neuronal control of sweat gland stem cell fate. Completion of our proposed studies will provide novel insights into molecular mechanisms by which nervous system influence sweat gland morphogenesis and cell fate determination at different developmental stages. Further, our results will provide groundbreaking insight into how sweat glands and nerves co-develop into a functional unit, which will in turn facilitate regenerative therapies for patients suffering from sweating deficiency.