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: 10273461
• 负责人: Andrew C White
• 金额: $ 15.66万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273461
• 关键词: Antibodies; Architecture; Biological Models; Biology; Cells; Chromatin Remodeling Factor; Cutaneous; Cytokine Signaling; DNA Damage; Data; Dependence; Development; Disease; Epidermis; Event; 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; 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; stem cell migration; stem cell population; stem cell proliferation; stem cells; transcriptomics; treatment strategy; 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 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.

项目摘要 /摘要 毛囊的黑素细胞干细胞（MCSC）可以用作黑素细胞补充的储层 对皮肤的表皮层已被证明 疾病白癜风，其中在毛囊周围以圆周图案发现了新的色素沉着， 不幸的是，用狭窄的紫外线B辐射（UVB）。 另一方面 黑色素瘤，皮肤癌的日期。 为了响应UVB的暴露，我们的长期目标是确定分子机制 改变MCSC的激活和迁移，以最终的主要影响，从而取得了重大影响 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，由UVB暴露引起的皮肤中的促炎状态， 我们也从突变体MCSC中促进了MCSC易位和黑色素瘤的启动 表明建筑染色质重塑因子HMGA2中功能的丧失导致两者的损害 MCSC易位和黑色素瘤通过细胞外部机制 炎症和HMGA2常规过程的事件尚未进行 信号传导和中性粒细胞/巨噬细胞募集已被确定为MCSC的潜在介体 从MCSC进行了迁移和迁移，这是其中的中心假设。 UVB介导的MCSC易位和来自MCSC的黑色素瘤的启动需要炎症细胞涌入 和TNF信号，由组织特异性HMGA2转录调控诱导。 在此提案中，我们将测试特定的单元受欢迎和信号通路是否是响应 UVB介导的MCSC易位和通过AIM启动的MCSC易位和黑色素瘤启动1）导致炎症的必要性 中性粒细胞和巨噬细胞的介导的招募，目标2） TNF介导的细胞因子信号传导，目标3）旨在定义细胞种群和下游 转录的变化取决于HMGA2。 这些过程在体内，使用细胞特异性遗传操作，抗体和小的划分/过表达 细胞群体和信号通路的分子中和，以及分离的细胞上的转录组学分析 普及。 在UVB介导的MCSC易位和黑色素瘤开始期间，将导致测试新型策略 白癜风治疗和预防黑色素瘤。 改善患有皮肤疾病的患者的健康。