Nerve-stem cell interactions during skin homeostasis and wound repair

项目摘要 皮肤经历更新和再生的恒定周期，这取决于多个干细胞群 用于维持其作为屏障和环境传感器的功能。位于环境界面， 皮肤干细胞必须能够适应在系统水平上检测到的变化以保持皮肤功能。如何 系统信息的整合，以调节皮肤干细胞的行为仍然知之甚少。的 交感神经系统（SNS）密集地支配皮肤，并与三个关键茎形成连接 皮肤中的细胞群，为了解干细胞活性如何直接影响 由身体的系统性变化引起并与之相结合。作为一个地方和系统的监管机构，SNS是独一无二的 将生物体水平上的变化与外周干细胞的变化联系起来。SNS是 自主神经系统的一个分支，并在基础水平上持续活跃，以调节生理 过程，如心率和血压，但在压力下变得高度升高，引发战斗或 飞行反应。传统上，交感神经元被认为只直接调节兴奋性细胞， 然而，造血干细胞和皮肤干细胞的开创性研究表明，交感神经活动具有重要的生物学意义。 通过直接调节干细胞来发挥更广泛的生理作用。此外，交感神经病变（丧失 神经支配）与伤口愈合时间延长有关，这表明交感神经活动的重要作用 在皮肤修复方面。皮肤的最外层由不断更新的表皮组成， 关键的皮肤干细胞，表皮干细胞（EpSC），用于周转和修复。EpSC活性必须 特别受到监管，因为它们极易受到环境致癌物的影响，如紫外线， 导致一些最常见的皮肤癌类型的发展。尽管它的重要性， 在局部和系统水平上，对由外部信号调节的免疫调节机制知之甚少。在皮肤局部， 交感神经元支配EpSC，初步结果表明交感神经递质， 去甲肾上腺素能够刺激EpSC增殖。根据这些结果，我认为交感神经活动 直接调节EpSC行为以控制损伤后的表皮更新和修复。我会利用 在小鼠模型中使用药理学和化学遗传学工具， 确定交感神经系统如何在表皮更新和修复过程中调节EpSCs。我也会 确定这是否直接通过激活EpSCs表达的去甲肾上腺素受体Adrb 2而发生 并确定Adrb2信号传导下游的分子通路。这一建议将阐明细胞 SNS调节表皮更新和愈合的机制，并评估治疗潜力 利用Adrb2来完成这些过程。由于许多药理学试剂可用于调节交感神经 活性，从这个建议的结果可以迅速转化为各种皮肤疾病的治疗。

PROJECT ABSTRACT The skin undergoes constant cycles of renewal and regeneration, depending on multiple stem cell populations for the maintenance of its function as a barrier and environmental sensor. Situated at the environmental interface, skin stem cells must be able to adapt to changes detected at the systemic level to preserve skin function. How systemic information is integrated to regulate skin stem cell behavior remains poorly understood. The sympathetic nervous system (SNS) densely innervates the skin, and forms connections with the three key stem cell populations in the skin, providing a starting point for understanding how stem cell activity is directly influenced by and integrated with systemic changes in the body. As both a local and systemic regulator, the SNS is uniquely positioned to link changes sensed at the organismal level to changes in stems cell in the periphery. The SNS is a branch of the autonomic nervous system, and is constantly active at a basal level to modulate physiological processes such as heart rate and blood pressure, but becomes highly elevated under stress to trigger fight-or flight responses. Traditionally, sympathetic neurons were thought to only directly regulate excitatory cells such as muscle; however, pioneering studies in hematopoietic and skin stem cells indicate sympathetic activity has a wider role governing physiology by directly regulating stem cells. Additionally, sympathetic neuropathy (loss of innervation) in the skin is associated with prolonged wound healing, suggesting a vital role for sympathetic activity in skin repair. The outermost layer of the skin consists of a continually renewing epidermis that depends on one of the key skin stem cells, epidermal stem cells (EpSCs), for turnover and repair. EpSC activity must be exceptionally regulated as they are extremely vulnerable to environmental carcinogens such as UV light that can lead to development of some of the most prevalent types of skin cancer. Despite its importance, how EpSCs are regulated by extrinsic signals, both at the local and systemic level, is poorly understood. Locally in the skin, sympathetic neurons innervate EpSCs, with preliminary results indicating the sympathetic neurotransmitter, norepinephrine, is able to stimulate EpSC proliferation. Given these results, I propose sympathetic activity directly regulates EpSC behavior to govern epidermal renewal and repair following injury. I will utilize pharmacological and chemogenetic tools in a mouse model that permits tracing of EpSCs and progeny to determine how the sympathetic nervous system regulates EpSCs during epidermal renewal and repair. I will also determine if this occurs directly through activation of the norepinephrine receptor, Adrb2, expressed by EpSCs and identify the molecular pathways downstream of Adrb2 signaling. This proposal will elucidate the cellular mechanisms by which the SNS regulates epidermal renewal and healing, and evaluate the therapeutic potential of harnessing Adrb2 for these processes. As many pharmacologic agents are available to modulate sympathetic activity, results from this proposal could be rapidly translated into treatments for a variety of skin diseases.