Pathogenic T cells in discoid lupus erythematosus

盘状红斑狼疮中的致病性 T 细胞

• 批准号: 10664134
• 负责人: ALICIA LITTLE
• 金额: $ 17.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664134
• 关键词: Address; Adoptive Transfer; Advisory Committees; Affect; African American; Alopecia; Atrophic; Autoimmune; Autoimmune Diseases; Bar Codes; Biometry; Blood; Blood specimen; Bone Marrow; Cell Separation; Cell Survival; Cells; Cellular biology; Chimera organism; Chronic; Cicatrix; Clonal Expansion; Clone Cells; Cutaneous; Cytotoxic T-Lymphocytes; Data; Dermatology; Development; Diagnosis; Discoid Lupus Erythematosus; Disease; Environment; FOXP3 gene; Flow Cytometry; Fluorescent in Situ Hybridization; Future; Gene Expression Profile; Genes; Granzyme; Head and neck structure; Human; Hypopigmentation; Hypoxia; Hypoxia Inducible Factor; Imaging Techniques; Immunobiology; Immunofluorescence Immunologic; Immunologics; Impairment; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Kidney; Laboratories; Lesion; Lupus; Maps; Mediating; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; PTPRC gene; Pathogenicity; Pathway interactions; Patients; Phenotype; Physicians; Population; Production; Quality of life; Regulatory T-Lymphocyte; Research; Role; Scientist; Signal Transduction; Site; Skin; Skin Tissue; Systemic Lupus Erythematosus; Systemic disease; T cell infiltration; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Tissues; Training; Translational Research; Woman; Work; antagonist; career development; clinical investigation; comparative; cytokine; cytotoxic; cytotoxicity; draining lymph node; effector T cell; exhaustion; genetic signature; hypoxia inducible factor 1; immune cell infiltrate; lupus prone mice; mortality; mouse model; new therapeutic target; novel; novel therapeutics; pharmacologic; programs; reconstitution; research study; response; single-cell RNA sequencing; skin damage; skin disorder; skin lesion; targeted treatment; tissue injury; transcription factor; transcriptomics; translational immunology

PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with a predilection for affecting the head and neck that causes permanent scarring, hypopigmentation, and alopecia. DLE disproportionately affects African American women, and it severely impairs quality of life. DLE may occur alone or in the setting of systemic lupus erythematosus (SLE), and treatments for DLE are currently unsatisfactory. The DLE inflammatory infiltrate is predominantly composed of T cells, which appear to promote tissue inflammation and damage, but how they adapt to the skin environment and subsequently promote tissue injury is unknown. We recently identified an inflammatory gene program induced by the transcription factor hypoxia inducible factor (HIF) that is necessary for the survival and effector ability of pathogenic T cells in lupus-prone mice, with a similar program upregulated in human SLE. Yet, how HIF1 promotes damage and what other tissue adaptation and effector pathways are activated in skin-infiltrating T cells in DLE are not known. Based on my preliminary studies, I hypothesize that HIF1 regulates pathogenic T cell survival and effector function in DLE skin, causing inflammation and damage that may be mediated in part by enhanced cytotoxicity. This HIF1-regulated effector program also suggests a paradigm of pathogenic adaptation in tissue-infiltrating T cells with the potential to drive tissue damage. To test my hypothesis, I will determine the mechanism of HIF1 blockade in alleviating skin disease in a murine lupus model. I will also study human DLE skin and blood samples using single cell RNA sequencing to probe the developmental trajectory, phenotypic, and functional profile of T cells in human DLE. Finally, I will use imaging techniques to examine the role of cytotoxicity in tissue damage in human DLE, with parallel studies in mouse tissue. My studies will not only elucidate the role of HIF1 and cytotoxicity in DLE, but will also yield the first detailed characterization of infiltrating and circulating T cells in human DLE, paving the way for future studies to develop and evaluate novel therapeutics for this devastating disease. My proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Joseph Craft, a leader in the fields of lupus research and T cell biology. Dr. Craft's laboratory in the Yale Department of Immunobiology provides a highly collaborative and supportive research environment. To further support my training, I have assembled an advisory committee with experts in transcriptomic analyses, translational dermatology, cutaneous T cell biology, and autoimmune skin disease. My research studies and directed additional career development activities focused on computational approaches, human translational research, and biostatistics in clinical investigation will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study cutaneous autoimmune diseases including DLE.

项目概要 盘状红斑狼疮 (DLE) 是一种毁容性自身免疫性皮肤病，容易影响 头部和颈部会导致永久性疤痕、色素沉着和脱发。 DLE 不成比例 影响非裔美国妇女，并严重损害生活质量。 DLE 可能单独发生或在以下情况下发生 系统性红斑狼疮（SLE）和 DLE 的治疗目前并不令人满意。数据LE 炎症浸润主要由 T 细胞组成，T 细胞似乎会促进组织炎症， 损伤，但它们如何适应皮肤环境并随后促进组织损伤尚不清楚。我们 最近发现了由转录因子缺氧诱导因子诱导的炎症基因程序 (HIF) 对于狼疮易感小鼠中致病性 T 细胞的生存和效应能力是必需的，具有 类似的程序在人类 SLE 中上调。然而，HIF1 如何促进损伤以及其他组织适应 DLE 中皮肤浸润 T 细胞的激活和效应途径尚不清楚。根据我的初步 研究中，我假设 HIF1 调节 DLE 皮肤中的致病性 T 细胞存活和效应器功能，从而导致 炎症和损伤可能部分是由增强的细胞毒性介导的。这种 HIF1 调节的效应器 该计划还提出了组织浸润 T 细胞的致病适应范式，有可能 驱动组织损伤。为了验证我的假设，我将确定 HIF1 阻断在缓解中的机制 小鼠狼疮模型中的皮肤病。我还将使用单细胞研究人类 DLE 皮肤和血液样本 RNA 测序可探测人类 T 细胞的发育轨迹、表型和功能概况 深度学习。最后，我将使用成像技术来检查细胞毒性在人类 DLE 组织损伤中的作用， 与小鼠组织的平行研究。我的研究不仅会阐明 HIF1 和细胞毒性在 DLE 中的作用， 但也将首次获得人类 DLE 中浸润和循环 T 细胞的详细表征，为 未来研究开发和评估这种毁灭性疾病的新疗法的方法。我的建议 还将支持一段职业发展时期，在此期间我将接受基础和基础方面的额外培训 Joseph Craft 博士实验室的转化免疫学，Joseph Craft 博士是狼疮研究和 T 领域的领导者 细胞生物学。 Craft 博士位于耶鲁大学免疫生物学系的实验室提供了高度协作和 支持性的研究环境。为了进一步支持我的培训，我组建了一个咨询委员会 转录组分析、转化皮肤病学、皮肤 T 细胞生物学和自身免疫性皮肤专家 疾病。我的研究并指导了其他专注于计算的职业发展活动 临床研究中的方法、人类转化研究和生物统计学将使我能够 作为一名医师科学家成功实现了研究独立性，并开设了自己的实验室，这样我就可以 使用基本和转化免疫学方法来研究皮肤自身免疫性疾病，包括 DLE。