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.

项目摘要 盘状红斑狼疮（DLE）是一种毁容的自身免疫性皮肤疾病，偏爱影响 导致永久性疤痕，不形成和脱发的头颈。不成比例 影响非裔美国妇女，并严重损害生活质量。 DLE可能单独或在 全身性红斑狼疮（SLE）和DLE的处理目前不令人满意。 DLE 炎性浸润主要由T细胞组成，T细胞似乎促进了组织炎症和 损坏，但是它们如何适应皮肤环境并随后促进组织损伤是未知的。我们 最近确定了由转录因子缺氧诱导因子引起的炎症基因程序 （HIF）是狼疮易发的病原T细胞生存和效应子的必要条件，具有A 类似的程序在人SLE中上调。但是，HIF1如何促进损害和其他组织适应 尚不清楚在DLE中浸入皮肤的T细胞中激活效应子途径。根据我的初步 研究，我假设HIF1调节DLE皮肤中的致病性T细胞存活和效应子功能，从而导致 炎症和损害可能部分通过增强的细胞毒性介导。该HIF1调节的效应子 程序还表明，在组织浸入T细胞中的致病性适应范式具有潜力 驱动组织损伤。为了检验我的假设，我将确定HIF1封锁的机制减轻 鼠狼疮模型中的皮肤病。我还将使用单细胞研究人类的皮肤和血液样本 RNA测序以探测人类T细胞的发育轨迹，表型和功能谱 DLE。最后，我将使用成像技术检查细胞毒性在人DLE中组织损伤中的作用， 在小鼠组织中进行平行研究。我的研究不仅会阐明HIF1和细胞毒性在DLE中的作用， 但也将产生人类DLE中浸润和循环T细胞的第一个详细表征，铺路 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 还将支持一个职业发展时期，在此期间我将接受基本和 约瑟夫·克拉夫特（Joseph Craft）博士的转化免疫学，狼疮研究领域的领导者 细胞生物学。耶鲁大学免疫生物学系的Craft博士实验室提供了高度协作和 支持性研究环境。为了进一步支持我的培训，我已与 转录组分析，翻译皮肤病学，皮肤T细胞生物学和自身免疫性皮肤专家 疾病。我的研究研究并指导了其他职业发展活动，重点是计算 临床研究中的方法，人类翻译研究和生物统计学将使我能够 成功地作为医师科学家实现研究独立性，并开设自己的实验室，以便我可以 使用基本和转化的免疫方法研究包括DLE在内的皮肤自身免疫性疾病。