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

皮肤 UVB 照射下黑色素细胞干细胞迁移和黑色素瘤起始的调节因子

• 批准号: 10004336
• 负责人: Andrew C White
• 金额: $ 33.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004336
• 关键词: Antibodies; Architecture; Biological Models; Biology; Cell Proliferation; Cells; Chromatin Remodeling Factor; Cutaneous; Cytokine Signaling; DNA Damage; Data; Dependence; Development; Disease; Epidermis; Genetic Transcription; Goals; Hair follicle structure; Health; Human; Immunology; Impairment; Inflammation; Inflammatory; Knowledge; Lesion; Mediating; Mediator of activation protein; Melanins; Methods; Microbiology; Mission; Mole the mammal; Molecular; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Neutrophil Infiltration; Patients; Pattern; Pigmentation physiologic function; Pigments; Population; Prevention; Process; Property; Public Health; Radiation exposure; Radiation therapy; Reporting; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Source; Stem cells; TNF gene; Testing; Tissues; Transcriptional Regulation; UVB induced; Ultraviolet B Radiation; Vitiligo; Work; cell behavior; cell motility; cell type; experience; genetic manipulation; improved; in vivo; innovation; irradiation; loss of function; macrophage; melanocyte; melanoma; migration; mutant; neutrophil; novel strategies; novel therapeutics; overexpression; recruit; response; skin disorder; small molecule; stem cell biology; transcriptomics; tumor; tumor initiation; tumorigenic; ultraviolet; ultraviolet irradiation

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.

项目概要/摘要 毛囊的黑色素细胞干细胞（McSC）可以作为黑色素细胞补充的储存库 到皮肤的表皮层。这种特性已在色素脱失患者中得到证实 白癜风病，在毛囊周围的毛囊周围图案中发现新的色素沉着， 经过窄带紫外线 B 辐射 (UVB) 治疗后。不幸的是，通过重新染色 UVB 疗法既不广泛也不持久。另一方面，携带突变的 McSC 可以作为 黑色素瘤的起源细胞，黑色素瘤是最致命的皮肤癌。在这种情况下，黑色素瘤可以由 McSC 响应 UVB 照射而激活。识别分子是我们的长期目标 UVB 的机制改变了 McSC 的激活和迁移，以提供重要的 影响导致白癜风治疗的改善和黑色素瘤预防的新方法。 我们的初步数据表明，由 UVB 暴露引起的皮肤促炎状态， 促进 McSC 易位至表皮，并促进突变 McSC 引发黑色素瘤。我们还有 研究表明，结构染色质重塑因子 Hmga2 的功能丧失会导致 McSC 易位和黑色素瘤起始。其潜在的分子机制 炎症和 Hmga2 调节这些过程的机制尚未确定。 TNF 信号传导和 中性粒细胞/巨噬细胞募集已被确定为 McSC 增殖的潜在介质 McSC 的迁移和黑色素瘤起始。该提案的中心假设是 UVB- 介导的 McSC 易位以及 McSC 引发黑色素瘤需要炎症细胞流入和 TNF 信号传导，由组织特异性 Hmga2 转录调控诱导。 在这个提案中，我们将测试特定的细胞群和信号通路是否负责 对于 UVB 介导的 McSC 易位和黑色素瘤起始，通过目标 1）针对必要性 炎症介导中性粒细胞和巨噬细胞的募集，目标 2）针对必要性和 Tnf 介导的细胞因子信号传导的充分性，以及目标 3) 旨在定义细胞群和 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 通过细胞特异性基因操作进行删除/过度表达来定义体内这些过程的系统， 细胞群和信号通路的抗体和小分子中和，以及转录组学 对分离的细胞群进行分析。了解并最终定义细胞群和 UVB 介导的 McSC 易位和黑色素瘤发生过程中发生的转录组变化将 能够测试白癜风治疗和黑色素瘤预防的新策略。这些目标直接在 符合 NIAMS 改善皮肤病患者健康的使命。