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， 采用窄带紫外线B辐射(UVB)治疗。不幸的是，通过UVB疗法恢复色素沉着 既不广泛也不持久。另一方面，携带突变的骨髓间充质干细胞可以作为 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 作为对UVB暴露的回应。我们的长期目标是确定UVB通过 改变McSCs的激活和迁移，最终提供导致改善的重大影响 白癜风的治疗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功能的丧失会导致两者的损害 MCSC易位与黑色素瘤发生的细胞外在机制。潜在的分子 炎症和HMGA2调节这些过程的事件尚未确定。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的潜在介质 骨髓间充质干细胞的增殖和迁移以及黑色素瘤的起源。这是这一提议的中心假设 UVB介导的MCSC易位，以及McSCs引发的黑色素瘤，需要炎性细胞的进入 以及由组织特异性HMGA2转录调控诱导的肿瘤坏死因子信号。 在这项提议中，我们将测试特定的细胞群体和信号通路是否负责 UVB介导的MCSC易位和黑色素瘤的发生 中性粒细胞和巨噬细胞的中介募集，目标2)针对以下因素的必要性和充分性 由肿瘤坏死因子介导的细胞因子信号转导，目的是定义细胞群体和下游 转录变化依赖于HMGA2。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，利用细胞特异性的基因操作、抗体和小分子的缺失/过表达 细胞群体和信号通路的分子中和，以及分离细胞的转录图谱 人口。理解并最终确定细胞群体和正在发生的转录变化 在UVB介导的MCSC易位和黑色素瘤启动过程中，将导致测试新的治疗策略 白癜风的治疗和黑色素瘤的预防。这些目标与NIAMS的使命直接一致 改善皮肤病患者的健康状况。

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, 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.