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.

总体而言——项目概要 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 复杂组织内的灰化。白癜风是一种皮肤自身免疫性疾病，其中细胞毒性 CD8+ T 细胞靶向 产生色素的黑素细胞，会导致毁容的白斑，这对那些人来说尤其具有破坏性 皮肤较黑。白癜风是研究器官特异性自身免疫机制的理想疾病 因为疾病表型可以与分子途径直接相关。也就是说，受影响的皮肤可能是 服务和采样，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 1 型糖尿病和多发性硬化症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。 在人类患者中进行研究更加困难。通过白癜风我们可以开发一个全面的 对器官特异性自身免疫在人体组织内进展的深入了解。 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 与邻近细胞相互作用，参与并破坏黑色素细胞，并建立自身免疫性的长期记忆 直接位于白癜风病灶内。我们生成了一组广泛的高分辨率、转化多组学数据 从白癜风患者皮肤中提取，并将其组装成多种细胞类型之间的集成通信网络 协调疾病进展。这为白癜风发病机制提供了线索，现在必须对其进行验证， 解剖并重新组装以揭示自身免疫的基本概念。因此，我们假设自动 反应性 T 细胞功能由表皮微环境内的细胞信号精心协调。 为了检验这一假设，我们将利用现有数据、由领先研究人员组成的多学科团队， 专为发现而设计的边缘工具，以及发现皮肤细胞如何协调自动免疫的创新策略 白癜风期间的社区。项目 1 将研究白癜风中的自身反应性 T 细胞功能，以确定自身反应如何 活性 T 细胞克隆多样性和定位定义临床疾病表型并协调黑素细胞 破坏。项目 2 将重点关注白癜风的细胞间通讯和组织记忆，以剖析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 以及白癜风病灶内的沟通。行政核心将促进沟通，确保科学 重点成果，并监督财政管理以支持重点研究目标和实施。 我们期望对协调的细胞通信和相互作用建立一个综合的理解 驱动白癜风发病机制。这将揭示自身免疫的基本机制并支持更好的治疗 针对这些毁灭性疾病的治疗方法。白癜风的独特特点以及我们的初步认识 大量数据、调查团队和创新计划为我们提供了无与伦比的发现机会。