Regulators of Melanocyte Stem Cell Migration and Melanoma Initiation in Response to Cutaneous UVB Irradiation

项目总结/摘要 毛囊中的黑素干细胞（McSCs）可以作为黑素细胞补充的储存库 皮肤的表皮层。这种性质已在色素脱失患者中得到证实。 疾病白癜风，其中新的色素沉着被发现在毛囊周围的毛囊周围模式，以下 用窄带紫外线B辐射（UVB）处理。不幸的是，通过UVB治疗的色素沉着 既不广泛也不持久。另一方面，携带突变的McSC可以作为细胞的起源， 黑色素瘤是最致命的皮肤癌在这种情况下，黑色素瘤可以通过激活McSCs来启动。 对UVB暴露的反应。我们的长期目标是确定UVB的分子机制， 改变McSCs的活化和迁移，最终产生显著影响， 白癜风治疗和黑色素瘤预防的新方法。 我们的初步数据表明，皮肤中的促炎状态，由UVB暴露诱导， 促进McSC易位至表皮和黑色素瘤从突变的McSC起始。我们还 显示结构染色质重塑因子Hmga 2的功能丧失导致两者的损伤， McSC易位和黑色素瘤启动通过细胞外源性机制。潜在的分子 炎症和Hmga 2调节这些过程的事件尚未确定。TNF 信号传导和中性粒细胞/巨噬细胞募集已被确定为McSC的潜在介导物 增殖和迁移以及从McSC引发黑素瘤。这是这个提议的核心假设 UVB介导的McSC易位和从McSC开始的黑色素瘤需要炎性细胞流入， 和TNF信号传导，其由组织特异性Hmga 2转录调节诱导。 在这项提案中，我们将测试特定的细胞群和信号通路是否负责 UVB介导的McSC易位和黑色素瘤通过针对炎症必要性的Aim 1）启动 介导的中性粒细胞和巨噬细胞的募集，目的2）针对的必要性和充分性， 由TNF-α介导的细胞因子信号传导，以及目的3），其旨在限定细胞群体和下游 转录变化依赖于Hmga 2。我们的方法将利用我们的创新模型系统来定义 这些过程在体内，使用通过细胞特异性遗传操作的缺失/过表达，抗体和小 细胞群体和信号传导途径的分子中和，以及分离细胞的转录组学分析 人口。了解并最终确定细胞群和转录组发生的变化 在UVB介导的McSC易位和黑色素瘤启动过程中， 白癜风治疗和黑色素瘤预防。这些目标直接符合NIAMS的使命， 改善皮肤病患者的健康。

PROJECT SUMMARY / ABSTRACT Melanocyte stem cells (McSCs) of the hair follicle can serve as a reservoir for melanocyte replenishment to the epidermal layer of the skin. This property has been demonstrated in patients with the depigmentation disease vitiligo, in which new pigmentation is found in a peri-follicular pattern surrounding hair follicles, following treatment with narrow-band ultraviolet B radiation (UVB). Unfortunately, repigmentation through UVB therapy is neither widespread nor durable. On the other hand, McSCs harboring mutations can serve as cells of origin for melanoma, the deadliest of skin cancers. Melanoma in this context can be initiated by the activation of McSCs in response to UVB exposure. It is our long-term goal to identify the molecular mechanisms through which UVB alters the activation and migration of McSCs to ultimately provide a significant impact leading to the improvement of vitiligo treatment and new methods of melanoma prevention. Our preliminary data indicate that a pro-inflammatory state in the skin, induced by UVB exposure, facilitates McSC translocation to the epidermis and melanoma initiation from mutant McSCs. We have also shown that loss of function in the architectural chromatin remodeling factor Hmga2 results in impairment of both McSC translocation and melanoma initiation through a cell extrinsic mechanism. The underlying molecular events through which inflammation and Hmga2 regulate these processes have not been identified. TNF signaling and neutrophil/macrophage recruitment have been determined as potential mediators of McSC proliferation and migration, and melanoma initiation from McSCs. It is the central hypothesis of this proposal that UVB-mediated McSC translocation, and melanoma initiation from McSCs, requires inflammatory cell influx and TNF signaling, which is induced by tissue-specific Hmga2 transcriptional regulation. In this proposal, we will test whether specific cell populations and signaling pathways are responsible for UVB-mediated McSC translocation and melanoma initiation via Aim 1) directed at the necessity of inflammation mediated recruitment of neutrophils and macrophages, Aim 2) directed at the necessity and sufficiency of cytokine signaling mediated by Tnf-alpha, and Aim 3) directed at defining the cell population and downstream transcription changes dependent upon Hmga2. Our approach will utilize our innovative model system to define these processes in vivo, using deletion/overexpression by cell specific genetic manipulation, antibody and small molecule neutralization of cell populations and signaling pathways, and transcriptomic profiling on isolated cell populations. Understanding and conclusively defining the cell populations and transcriptomic changes occurring during UVB-mediated McSC translocation and melanoma initiation will lead to testing of novel strategies for vitiligo treatment and melanoma prevention. These goals are directly in line with the mission at NIAMS to improve the health of patients suffering from skin diseases.