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: 10703370
• 负责人: John E Harris
• 金额: $ 166.21万
• 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/10703370
• 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; Center for Translational Science Activities; Characteristics; Clinical; Clone Cells; Communication; Complex; Computing Methodologies; Cues; Data; Disease; Disease Progression; Ensure; Epidermis; Fluorescent in Situ Hybridization; Genetic Risk; Goals; Human; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Knowledge; Lesion; Ligands; 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; novel therapeutic intervention; outreach; receptor; response; risk variant; single cell technology; skin disorder; tool; transcriptomics; translational goal

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， 在复杂的组织中。白癜风是一种自身免疫性皮肤疾病，其中细胞毒性CD 8 + T细胞靶向 制造色素的黑色素细胞，这会导致毁容的白色斑点，这对那些 肤色较深的人白癜风是研究器官特异性自身免疫机制的理想疾病 因为疾病表型与分子途径直接相关。也就是说，受影响的皮肤可以被... 提供服务和取样，靶细胞和抗原是已知的，并且转化研究工具是可用的。维蒂- ligo与自身免疫性疾病（如1型糖尿病和穆尔）共享遗传风险等位基因和其他机制。 在人类患者中进行研究更为困难。通过白癜风，我们可以开发一个压缩- 深入了解器官特异性自身免疫，因为它在人体组织内的进展。 我们的目标是确定自身反应性T细胞在皮肤中导航的机制， 与邻近的细胞，从事和破坏黑色素细胞，并创造长期记忆的自身免疫性疾病， 白癜风的症状有哪些？我们生成了一组广泛的高分辨率，翻译多组学数据， 并将其组装成多种细胞类型之间的集成通信网络 协调疾病的发展。这为白癜风的发病机制提供了线索，现在必须加以验证， 解剖和重组，以揭示自身免疫的基本概念。因此，我们假设，汽车- 反应性T细胞功能通过表皮微环境内的细胞信号仔细协调。 为了验证这一假设，我们将利用现有的数据，一个由领先的研究人员组成的多学科团队， 为发现而设计的边缘工具，以及一种发现皮肤细胞如何协调自身免疫的创新策略， 白癜风的危害有哪些？项目1将调查白癜风中的自身反应性T细胞功能，以确定自身反应性T细胞功能如何影响白癜风患者的免疫功能。 活性T细胞克隆多样性和定位定义了临床疾病表型，并协调黑素细胞 杀伤性项目2将重点关注白癜风的细胞间通讯和组织记忆， 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录组学研究核心的支持， 使用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 和交流。行政核心将促进沟通，确保科学， 确定研究成果，并监督财务管理，以支持研究目标和实施的重点。 我们希望建立一个协调的蜂窝通信和互动的综合理解， 驱白癜风发病机理。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方法。白癜风的治疗方法有哪些？ 少量的数据、调查团队和创新的计划为我们提供了前所未有的发现机会。