Mechanisms of IL-23 receptor-mediated pathogenicity in CD4+ T cells

IL-23受体介导的CD4 T细胞致病性机制

• 批准号: 10428485
• 负责人: Allen Wayne Ho
• 金额: $ 16.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428485
• 关键词: Activities of Daily Living; Address; Affect; Animal Model; Attention; Autoimmune; Autoimmune Diseases; Automobile Driving; Biology; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Cellular Immunology; Cellular biology; Characteristics; Cicatrix; Clinical; Colitis; Cutaneous; Cutaneous Involvement; Cutaneous Lupus Erythematosus; Data; Data Set; Dermatology; Development; Disease; Genes; Genetic Transcription; Genomics; Homeostasis; Hospitals; Immune; Immunologics; In Vitro; Inbred MRL lpr Mice; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Interleukin-17; Intestines; Investigation; Laboratories; Lesion; Lupus; Lupus Erythematosus; Maintenance; Mediating; Mentors; Molecular; Molecular Immunology; Mus; Organ; Pathogenesis; Pathogenicity; Patient Care; Patients; Phenotype; Physicians; Play; Population; Positioning Attribute; Production; Program Development; Protocols documentation; Quality of life; Receptor Signaling; Research; Role; Scientist; Signal Transduction; Skin; Socioeconomic Status; Study models; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Th1 Cells; Time; Tissues; Treatment Protocols; Woman; Work; career development; cytokine; effective therapy; experience; experimental study; improved; instructor; interleukin-23; lupus cutaneous; medical schools; mouse model; novel; optimal treatments; receptor; receptor expression; receptor function; skills; skin disorder; skin lesion; systemic autoimmune disease; targeted treatment; therapeutic target; whole genome

Project Summary/Abstract This proposal presents a five year research career development program focused on the study of the role of the IL-23 receptor (IL-23R) on CD4+ T cells in cutaneous lupus erythematosus (CLE). The candidate is currently an Instructor in Dermatology at Harvard Medical School in the Department of Dermatology at the Brigham and Women's Hospital. The outlined proposal builds upon the candidate's previous research and clinical experience in molecular and cellular immunology and cutaneous biology by leveraging the use of emerging genomic technologies within Dr. Vijay Kuchroo's, his primary mentor's, laboratory. The proposed experiments and didactic work will position the candidate with a unique set of cross disciplinary skills that will enable him to transition to independence as a physician scientist in autoimmune cutaneous biology. Cutaneous involvement is a major feature of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting multiple organs, but can also occur in the absence of systemic disease. Cutaneous lupus erythematosus (CLE) significantly impacts patients' quality of life, socioeconomic status, and can result in permanent scarring and dyspigmentation. Therefore, more effective therapies are critically required. However, our current understanding of CLE pathogenesis is limited, making the development of targeted therapies difficult. As a consequence, patient care can be negatively impacted as optimal treatment regimens cannot always be achieved. Therapies can improve the skin, systemic disease, both, or neither. Therefore, it is of critical importance that a better understanding of the basic immunologic underpinnings of CLE pathogenesis be achieved to meet this clinical need. This proposal aims to investigate the role of IL-23R expression on CD4+ T cells in the development of CLE. The proposed project will directly address this vital question while overcoming current limitations in the field. Aim 1 will examine the mechanisms by which the IL-23R confers pathogenicity to CD4+ T cells. Aim 2 tests whether the IL-23R confers pathogenicity to CD4+ T cells, which can then drive spontaneous skin inflammation in a mouse model of lupus erythematosus. Aim 3 leverages cutting edge genomic technologies and analysis to identify novel, transcriptionally distinct, pathogenic CD4+ T lymphocytes in the CLE lesional skin. Taken together, this project combines traditional molecular and cellular approaches with emerging genomic technologies and analysis to address a critically unmet need in cutaneous autoimmune disease.

项目摘要/摘要 这项建议提出了一项为期五年的研究职业发展计划，重点研究了 皮肤红斑狼疮(CLE)患者外周血中CD4+T细胞IL-23R的表达候选人目前是一名 哈佛医学院皮肤科讲师 女子医院。概述的建议建立在候选人以前的研究和临床经验的基础上 通过利用新兴基因组的使用，在分子和细胞免疫学和皮肤生物学方面 维贾伊·库奇鲁博士的主要导师的实验室里的技术。建议的实验和教学 工作将使应聘者拥有一套独特的跨学科技能，使他能够过渡到 独立于自身免疫性皮肤生物学的内科科学家。 皮肤受累是系统性红斑狼疮(SLE)的一个主要特征，SLE是一种系统性自身免疫性疾病 疾病影响多个器官，但也可在没有全身性疾病的情况下发生。皮肤性狼疮 红斑狼疮(CLE)显著影响患者的生活质量、社会经济地位，并可导致 永久性的疤痕和色素沉着。因此，迫切需要更有效的治疗方法。然而， 我们目前对CLE发病机制的认识有限，使得靶向治疗的发展受到限制 很难。因此，患者护理可能会受到负面影响，因为最佳治疗方案不能 总是能实现的。治疗可以改善皮肤或全身疾病，两者兼而有之，或者两者都不改善。因此，它是至关重要的 更好地了解CLE发病的基本免疫学基础的重要性 实现了满足这一临床需求。本研究旨在探讨IL-23R在CD4+T细胞中的作用。 细胞在CLE发生发展中的作用。拟议的项目将直接解决这一关键问题，同时克服 目前该领域的限制。目标1将检查IL-23R赋予致病性的机制 CD4+T细胞。目的2测试IL-23R是否赋予CD4+T细胞致病性，然后使其能够驱动 红斑狼疮小鼠模型中的自发性皮肤炎症。AIM 3利用尖端基因组 识别CLE中新的、转录上不同的致病CD4+T淋巴细胞的技术和分析 皮损皮肤。综上所述，该项目将传统的分子和细胞方法与新兴的 基因组技术和分析，以解决皮肤自身免疫性疾病中一个严重未得到满足的需求。