Determining how local factors influence repigmentation in stable vitiligo

确定局部因素如何影响稳定型白癜风的色素沉着

• 批准号: 10740267
• 负责人: Jessica Shiu
• 金额: $ 17.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740267
• 关键词: Affect; Aftercare; Area; Autoimmune; Biology; Biopsy; CD8-Positive T-Lymphocytes; CXCL9 gene; CXCR3 gene; Cell Communication; Cell model; Cells; Cellular Stress; Cellular biology; Chronic; Combined Modality Therapy; Consumption; Cutaneous; Dermatology; Development; Disease; Doctor of Philosophy; Environment; Equilibrium; Funding; Gene Expression; Genomics; Hair follicle structure; Homeostasis; Image; Immune; Immune response; Immunity; Immunosuppressive Agents; Inflammation; Injury; Left; Lesion; Location; Maps; Measures; Mentors; Metabolic; Methods; Modeling; Patient imaging; Patients; Phototherapy; Physicians; Pigmentation physiologic function; Pigments; Population; Population Dynamics; Positioning Attribute; Process; Publishing; Research; Research Personnel; Resistance; Resources; Scientist; Shapes; Signal Induction; Signal Transduction; Skin; Steroids; Stress; T-Cell Activation; T-Lymphocyte; Technical Expertise; Testing; Thromboplastin; Time; Training; Ultraviolet B Radiation; Vitiligo; WNT Signaling Pathway; Work; autoreactivity; chemokine; density; design; experience; in vivo imaging; insight; keratinocyte; melanocyte; microscopic imaging; migration; mouse model; multiphoton microscopy; non-invasive imaging; novel therapeutics; psychological distress; recruit; response; single-cell RNA sequencing; skin disorder; standard care; transcriptomics; treatment response; ultraviolet; wound

PROJECT SUMMARY/ ABSTRACT: Vitiligo is an autoimmune skin disease characterized by the progressive destruction of melanocytes by autoreactive CD8+ T cells, resulting in disfiguring patches of white depigmented skin that cause significant psychological distress among patients. The gold standard treatment involves narrow band ultraviolet B (NBUVB) therapy, which induces the migration of hair follicle melanocyte precursors, in conjunction with topical steroids to suppress the local immune. Unfortunately, treatment is time consuming and re-pigmentation is often uneven. It is unknown why some depigmented areas persist and others re-pigment within the same lesion. Our recent work using non-invasive multiphoton microscopy (MPM) and single-cell RNA sequencing (scRNA-seq) has demonstrated that a subpopulation of keratinocytes enriched in vitiligo skin is important in disease persistence. We termed these cells ‘stress keratinocytes’ as they upregulate molecules associated with inflammation, wounding and other injuries. In this K08 application, we propose to study how local signals from keratinocytes interact with T cells and melanocytes to drive vitiligo persistence and repigmentation after treatment. Using MPM imaging, scRNA-seq and spatial transcriptomics, we will define if stress keratinocytes signals to T cells and paucity of melanocyte recruiting factors are enriched in treatment resistant areas (specific aim 1). We will also compare test to see whether adding these factors locally is sufficient to promote repigmentation (specific aim 2). Completion of this work will define how local tissue factors shape immune responses and melanocyte homeostasis in the skin has implications beyond vitiligo. This K08 application is designed to provide Dr. Jessica Shiu, MD PhD, the scientific training and professional development necessary to become an independent R01-funded investigator in the field of cutaneous biology. She will be mentored by Dr. Anand Ganesan, a physician scientist and a pigment cell biology expert with expertise on single cell genomics and skin imaging. Her secondary mentors, Drs. Bogi Andersen and Qing Nie, have extensive experience in keratinocyte biology and single-cell RNA sequencing analyses. Additional scientists, Drs. Mihaela Balu and Tinoco will provide further expertise in noninvasive imaging and cutaneous immunity. The work takes place within the outstanding scientific environment at UCI in the Department of Dermatology and Skin Biology Resource Center and has the support of multiple state-of-the-art centers including the NSF-Simons Center for Multiscale Cell Fate Research and Genomics High Throughput Facility. This training plan will help her develop technical skills on noninvasive imaging and spatial transcriptomics as well as quantitative methods needed for the analysis of dynamic populations of keratinocytes so that she will be positioned as a leading physician scientist in the field of cutaneous biology.

项目总结/摘要： 白癜风是一种自身免疫性皮肤病，其特征是黑素细胞的进行性破坏， 自身反应性CD 8 + T细胞，导致白色脱色皮肤的毁容斑块， 患者的心理困扰。金标准治疗包括窄带紫外线B （NBUVB）疗法，其诱导毛囊黑素细胞前体的迁移，结合局部施用， 类固醇来抑制局部免疫不幸的是，治疗很耗时，而且经常需要重新色素沉着 不均匀。目前尚不清楚为什么一些脱色区域持续存在，而其他区域在同一病变内重新着色。我们 最近的工作使用非侵入性多光子显微镜（MPM）和单细胞RNA测序（scRNA-seq） 已经证明白癜风皮肤中富含的角质形成细胞亚群在疾病中是重要的， 坚持不懈我们称这些细胞为“应激角质形成细胞”，因为它们上调与 炎症、创伤和其他损伤。在这个K 08应用程序中，我们建议研究如何从本地信号 角质形成细胞与T细胞和黑色素细胞相互作用， 治疗使用MPM成像，scRNA-seq和空间转录组学，我们将确定是否应激角质形成细胞， T细胞的信号和缺乏黑素细胞募集因子在治疗抗性区域富集 （具体目标1）。我们还将进行比较测试，看看在本地添加这些因素是否足以促进 再色素沉着（具体目标2）。这项工作的完成将定义局部组织因子如何塑造免疫 皮肤中的黑素细胞反应和稳态的影响超出了白癜风。 此K 08应用程序旨在为Jessica Shiu博士，医学博士，科学培训和专业 发展必要的成为一个独立的R 01资助的研究人员在皮肤生物学领域。 她将由医生科学家和色素细胞生物学专家Anand Ganesan博士指导， 单细胞基因组学和皮肤成像的专业知识。她的第二位导师，博吉·安德森博士和聂青， 在角质形成细胞生物学和单细胞RNA测序分析方面拥有丰富的经验。额外 科学家，Mihaela Balu博士和Tinoco博士将在非侵入性成像和皮肤 免疫力这项工作发生在UCI杰出的科学环境中， 皮肤病学和皮肤生物学资源中心，并拥有多个最先进的中心的支持 包括NSF-Simons多尺度细胞命运研究中心和基因组学高通量设施。 该培训计划将帮助她发展非侵入性成像和空间转录组学方面的技术技能， 以及分析角质形成细胞动态群体所需的定量方法， 被定位为皮肤生物学领域的领先医生科学家。