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

项目摘要/摘要 毛囊的黑素细胞干细胞(McSCs)可以作为黑素细胞补充的储存库。 到皮肤的表皮层。这一特性已在色素脱失的患者中得到证实。 白癜风，在毛囊周围的毛囊周围发现新的色素沉着， 在接受窄带紫外线B辐射(UVB)治疗后。不幸的是，通过 UVB疗法既不广泛，也不持久。另一方面，携带突变的McSCs可以作为 黑色素瘤的起源细胞，是最致命的皮肤癌。在这种情况下，黑色素瘤可以由 对UVB暴露的反应激活McSCs。我们的长期目标是确定分子 机制通过UVB改变McSCs的激活和迁移，以提供显著的 带来了白癜风治疗的改进和黑色素瘤预防的新方法。 我们的初步数据表明，由UVB照射引起的皮肤中的促炎状态， 促进MCSC转位到表皮，并促进突变的McSCs引发黑色素瘤。我们还有 研究表明，结构染色质重塑因子HMGA2功能的丧失会导致 MCSC易位与黑色素瘤的发生。潜在的分子机制，通过它 炎症和HMGA2调节这些过程尚未确定。肿瘤坏死因子信号转导和 中性粒细胞/巨噬细胞募集已被确定为MCSC增殖和 骨髓间充质干细胞的迁移和黑色素瘤的发生。这一提议的中心假设是UVB- 介导的MCSC易位和由McSCs引发的黑色素瘤需要炎性细胞的进入和 组织特异性HMGA2转录调控所诱导的肿瘤坏死因子信号转导。 在这项提案中，我们将测试特定的细胞群体和信号通路是否起作用 针对UVB介导的MCSC易位和通过AIM 1)启动黑色素瘤的必要性 炎症介导的中性粒细胞和巨噬细胞的募集，目的2)针对必要性和 由肿瘤坏死因子介导的细胞因子信号的充分性，以及目标3)针对定义细胞群体和 下游转录的变化取决于HMGA2。我们的方法将利用我们的创新模式 在体内定义这些过程的系统，使用细胞特异性基因操作的缺失/过表达， 抗体和小分子中和细胞群体和信号通路，以及转录 对分离的细胞群体进行分析。了解并最终确定细胞群体和 UVB介导的MCSC易位和黑色素瘤起始过程中发生的转录变化 能够对白癜风治疗和黑色素瘤预防的新策略进行测试。这些目标直接在 与NIAMS改善皮肤病患者健康的使命相一致。

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 with UVB alters the activation and migration of McSCs in order to provide a significant impact resulting in 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. The underlying molecular mechanisms 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, 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 enable testing on 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.