A synthetic biosensor of immunologic synapse formation allowing multiplexed T cell antigen discovery for autoimmune neurologic disorders

一种免疫突触形成的合成生物传感器，可发现自身免疫性神经系统疾病的多重 T 细胞抗原

• 批准号: 10740610
• 负责人: JOSIAH GERDTS
• 金额: $ 18.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-23 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740610
• 关键词: Acceleration; Address; Affinity; Antibodies; Antigen Presentation Pathway; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmune encephalitis; Autoimmunity; Award; B-Lymphocytes; Binding; Biological Assay; Biology; Biosensor; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CNS autoimmune disease; California; Cell Communication; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Clinical Immunology; Clone Cells; Complex; Cytomegalovirus; Data Collection; Dedications; Detection; Development; Diagnosis; Disease; Doctor of Philosophy; Educational process of instructing; Encephalitis; Engineering; Environment; Faculty; Future; Goals; Human; ICAM1 gene; Immunity; Immunology; Immunosuppressive Agents; Individual; Infiltration; Infrastructure; Integrins; Knowledge; Laboratories; Lead; Libraries; Ligands; MHC Class I Genes; Measurement; Measures; Mechanics; Meningitis; Mentors; Mentorship; Methods; Molecular Conformation; Multiple Sclerosis; Nervous System Paraneoplastic Syndromes; Neurologist; Neurology; Pathogenesis; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Physicians; Physiological; Play; Postdoctoral Fellow; Precision therapeutics; Process; Production; Productivity; Proliferating; Proteins; Proteome; Research; Role; Safety; San Francisco; Scientist; Sensitivity and Specificity; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Therapeutic; Tissues; Training; Universities; Viral; Viral Antigens; Work; antigen detection; career development; cellular engineering; cytokine; design; diagnostic biomarker; experience; experimental study; future implementation; human disease; immunological synapse; immunological synapse formation; improved; innovation; intercellular communication; member; memory CD4 T lymphocyte; multiplex assay; nervous system disorder; neuroimmunology; new technology; next generation; novel; oligodendrocyte-myelin glycoprotein; pathogenic autoantibodies; peripheral blood; professor; programs; response; screening; sensor; sensor technology; seropositive; synthetic biology; tool; translational research program

Summary/Abstract Candidate: I am a neurologist-scientist at UCSF with a long-term goal to lead an independent laboratory- based research program focused on T cell autoantigen targets in autoimmune neurologic diseases. The K08 application is key for my career development, providing me with (1) mentorship from an accomplished team of scientists and physician-scientists, (2) dedicated teaching to expand my knowledge in basic and clinical immunology and synthetic biology (3) extensive hands-on training in biosensor engineering and T cell Ag detection, and (4) data collection for an R01 application. Research: T cells are important contributors to autoimmune neurological disorders including MS, MOGAD, and autoimmune encephalitis. Deeper understanding of pathogenesis is needed to develop more precise therapeutics that promise both improved efficacy and better safety profiles relative to broad-based immunosuppressant medications currently used. While high throughput methods for antibody discovery have transformed the field of autoimmune neurology by producing crucial diagnostic biomarkers, T cell Ags remain largely undefined given the lack of high throughput T cell Ag discovery platforms. This knowledge gap is significant given that T cells play important roles in disease pathogenesis. The current proposal introduces a novel technology to address the challenge of simultaneously evaluating many candidate Ags against a diverse T cell repertoire, which is based on an engineered biosensor that detects immune synapse formation at the single cell level, allowing multiplexed analysis. This proposal outlines the first experiments to further develop immune synapse sensing technology for the purposes of Ag discovery in autoimmune T cells. Mentorship and Training: My training will be accomplished through formal coursework and under direct mentorship of world leaders including Wendell Lim, PhD, who has extensive expertise in synthetic biology and cell engineering technologies. Professor Lim has over his 20 years at UCSF mentored ~50 postdoctoral fellows as well as 5 clinical fellows. I will be co-mentored by Scott Zamvil, MD/PhD and Michael Wilson MD, MAS, both physician-scientists with extensive experience in Neuroimmunology and autoimmune antigen biology. Environment: The University of California, San Francisco is an exceptional research environment with state- of-the-art facilities and world-renowned faculty. As a member of the UCSF Neurology Division of Neuroimmunology and Glial Biology and the UCSF Cell Design Institute, my work and training will bridge synthetic cell engineering and autoimmune Ag discovery. I will benefit from existing clinical autoantigen discovery infrastructure including the UCSF Center for Encephalitis & Meningitis led by Dr Wilson.

摘要/摘要 应聘者：我是加州大学旧金山分校的神经学家兼科学家，长期目标是领导一个独立的实验室- 基于研究计划的重点是自身免疫性神经疾病中的T细胞自身抗原靶标。K08 应用程序是我职业发展的关键，它为我提供了(1)来自一个成功的团队的指导 科学家和内科科学家，(2)致力于扩大我的基础和临床知识的教学 免疫学和合成生物学(3)生物传感器工程和T细胞抗原的广泛实践培训 检测，以及(4)R01应用的数据收集。 研究：T细胞是自身免疫性神经疾病的重要因素，包括MS，MOGAD， 和自身免疫性脑炎。需要对发病机制有更深入的了解，才能发展出更精确的 与广泛的基础治疗相比，承诺改善疗效和安全性的治疗 目前使用的免疫抑制药物。虽然高通量的抗体发现方法具有 通过产生关键的诊断生物标记物改变了自身免疫神经学领域，T细胞抗原仍然存在 由于缺乏高通量的T细胞抗原发现平台，很大程度上没有定义。这种知识鸿沟是 鉴于T细胞在疾病发病机制中发挥重要作用，这一点具有重要意义。目前的提案引入了一个 新技术可解决同时评估多个候选AGS与不同 T细胞谱系，这是基于一种工程生物传感器，检测免疫突触的形成 单细胞级别，允许多路分析。这份提案概述了进一步开发的第一批实验 免疫突触传感技术用于发现自身免疫T细胞中的抗原。 指导和培训：我的培训将通过正式的课程和指导下完成 指导包括温德尔·林博士在内的世界领导人，他在合成生物学和 细胞工程技术。林教授在加州大学旧金山分校工作了20年，指导了大约50名博士后研究员 以及5名临床研究员。我将由斯科特·赞维尔和迈克尔·威尔逊共同指导，他们都是医学博士/博士和迈克尔·威尔逊医学博士 内科医生--在神经免疫学和自身免疫抗原生物学方面有丰富经验的科学家。 环境：加州大学旧金山分校是一个特殊的研究环境，拥有州立大学- 一流的设施和世界知名的教师。作为加州大学旧金山分校神经科的一名成员 神经免疫学和神经胶质生物学与加州大学旧金山分校细胞设计院，我的工作和培训将架起桥梁 合成细胞工程和自身免疫性抗原的发现。我将受益于现有的临床自身抗原 发现基础设施，包括威尔逊博士领导的加州大学旧金山分校脑炎和脑膜炎中心。