Dissecting Functional Autoimmunity through High-Resolution Multiomics in a Vitiligo Center of Research Translation (V-CoRT)

白癜风研究转化中心 (V-CoRT) 通过高分辨率多组学剖析功能性自身免疫

• 批准号: 10404442
• 负责人: John E Harris
• 金额: $ 167.9万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404442
• 关键词: Achievement; Advanced Development; Affect; Affinity; Antigens; Architecture; Atlases; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological Assay; Biopsy; Cell Communication; Cell physiology; Cells; Cellular Assay; Characteristics; Clinical; Clone Cells; Communication; Complex; Computing Methodologies; Cues; Data; Disease; Disease Progression; Ensure; Epidermis; Fluorescent in Situ Hybridization; Foundations; Genetic Risk; Goals; Human; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Knowledge; Lesion; Ligands; Logistics; Maps; Memory; Modeling; Molecular; Monitor; Multiomic Data; Multiple Sclerosis; Organ; Pathogenesis; Pathway interactions; Patients; Pigments; Positioning Attribute; Recording of previous events; Research; Research Personnel; Resolution; Sampling; Series; Signal Transduction; Skin; Structure; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Translating; Translational Research; Vitiligo; White Spots; autoreactive T cell; cell type; chemokine; cytotoxic CD8 T cells; design; disease phenotype; human tissue; innovation; long term memory; melanocyte; multidisciplinary; multiple omics; outreach; receptor; response; risk variant; single cell technology; skin disorder; skin lesion; tool; transcriptomics

OVERALL – PROJECT SUMMARY Organ-specific autoimmunity requires a series of precise cellular interactions to coordinate target cell destruc- tion within complex tissues. Vitiligo is an autoimmune disease of the skin in which cytotoxic CD8+ T cells target pigment-making melanocytes, which results in disfiguring white spots that are particularly devastating for those with darker skin. Vitiligo is an ideal disease in which to investigate mechanisms of organ-specific autoimmunity because disease phenotype can be directly correlated to molecular pathways. That is, affected skin can be ob- served and sampled, target cells and antigens are known, and translational research tools are available. Viti- ligo shares genetic risk alleles and other mechanisms with autoimmune diseases like type 1 diabetes and mul- tiple sclerosis, which are more difficult to study in human patients. Through vitiligo we can develop a compre- hensive understanding of organ-specific autoimmunity as it progresses within human tissue. Our objective is to determine the mechanisms by which autoreactive T cells navigate the skin, communicate with neighboring cells, engage and destroy melanocytes, and create long-term memory of autoimmunity di- rectly within vitiligo lesions. We generated an extensive set of high-resolution, translational multiomics data from vitiligo patient skin and assembled it into an integrated communication network among multiple cell types that coordinate disease progression. This provides clues into vitiligo pathogenesis that must now be validated, dissected, and reassembled to reveal fundamental concepts of autoimmunity. Thus, we hypothesize that auto- reactive T cell function is carefully coordinated by cellular signals within the microenvironment of the epidermis. To test this hypothesis, we will leverage existing data, a multidisciplinary team of leading investigators, cutting edge tools designed for discovery, and an innovative strategy to discover how skin cells coordinate autoim- munity during vitiligo. Project 1 will investigate Autoreactive T cell Function in Vitiligo to determine how autore- active T cell clonal diversity and localization define the clinical disease phenotype and coordinate melanocyte destruction. Project 2 will focus on Cell-Cell Communications and Tissue Memory in Vitiligo to dissect the mechanisms by which ligand-receptor interactions coordinate T cell localization, function, and inflammatory memory. These projects will be supported by the High-Resolution Spatial Transcriptomics Research Core us- ing seq-FISH+ to translate our vitiligo multiomics data into a complete spatial understanding of cellular position and communication within vitiligo lesions. The Administrative Core will promote communication, ensure scien- tific achievement, and monitor fiscal management to support focus on research goals and implementation. We expect to create an integrated understanding of coordinated cellular communications and interactions that drive vitiligo pathogenesis. This will reveal fundamental mechanisms of autoimmunity and support better thera- peutic approaches for these devastating diseases. The unique characteristics of vitiligo as well as our prelimi- nary data, investigative team, and innovative plan provide us with an unparalleled opportunity for discovery.

总体--项目摘要 器官特异性自身免疫需要一系列精确的细胞相互作用来协调靶细胞的破坏。 在复杂的组织内运动。白癜风是一种以细胞毒性CD8+T细胞为靶点的皮肤自身免疫性疾病 制造色素的黑素细胞，这会导致毁容的白斑，这对那些 有着深色皮肤。白癜风是研究器官特异性自身免疫机制的理想疾病。 因为疾病表型可以直接与分子途径相关。也就是说，受影响的皮肤可能是- 提供和采样，靶细胞和抗原是已知的，翻译研究工具是可用的。维提- LIGO与1型糖尿病和多发性骨髓瘤等自身免疫性疾病具有相同的遗传风险等位基因和其他机制。 多发性硬化症，这在人类患者中更难研究。通过白癜风，我们可以开发出一种压缩- 对器官特异性自身免疫在人体组织内的进展有深入的了解。 我们的目标是确定自身反应性T细胞在皮肤中导航、交流的机制 与邻近细胞接触并摧毁黑素细胞，创造对自身免疫性疾病的长期记忆。 就在白癜风皮损内。我们生成了一组广泛的高分辨率、翻译多组学数据 从白癜风患者的皮肤中提取并组装成多种细胞类型之间的集成通信网络 来协调疾病的发展。这为白癜风的发病机制提供了线索，现在必须进行验证， 经过解剖和重组，揭示了自身免疫的基本概念。因此，我们假设自动- 反应性T细胞的功能是由表皮微环境中的细胞信号仔细协调的。 为了验证这一假设，我们将利用现有的数据，一个由领先调查人员组成的多学科团队， 为发现而设计的边缘工具，以及发现皮肤细胞如何协调自体的创新策略- 白癜风期间的社区生活。项目1将研究白癜风患者的自身反应性T细胞功能，以确定Autore- 活性T细胞克隆多样性和定位决定了临床疾病的表型，并协调了黑素细胞 毁灭。项目2将重点研究白癜风的细胞-细胞通信和组织记忆，以剖析 配体-受体相互作用协调T细胞定位、功能和炎症的机制 记忆。这些项目将得到高分辨率空间转译研究核心用户的支持- ING SEQ-FISH+将我们的白癜风多组学数据转化为对细胞位置的完整空间理解 以及白癜风皮损内的交流。行政核心将促进沟通，确保科学- 科技成果，并监督财务管理，以支持重点研究目标和实施。 我们希望建立对协调的蜂窝通信和交互的综合理解， 推动白癜风的发病机制。这将揭示自身免疫的基本机制，并支持更好的治疗。 治疗这些毁灭性疾病的传统方法。白癜风的独特特征以及我们的初步研究。 几乎没有数据、调查团队和创新计划为我们提供了一个无与伦比的发现机会。