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 候选人：我是UCSF的神经科医生科学家，其长期目标是领导独立的实验室 - 基于自身免疫性神经系统疾病中T细胞自动抗原靶标的研究计划。 K08 应用是我职业发展的关键，为我提供了一支成就团队的指导 科学家和医师科学家，（2）专门的教学，以扩大我在基本和临床方面的知识 免疫学和合成生物学（3）生物传感器工程和T细胞AG的广泛动手培训 检测和（4）R01应用程序的数据收集。 研究：T细胞是自身免疫性神经系统疾病的重要因素，包括MS，Mogad， 和自身免疫性脑炎。需要更深入地理解发病机理，以开发更精确的 相对于基于广泛的疗效和更好的安全性，可以提高疗效和更好的安全概况的治疗剂 当前使用的免疫抑制剂药物。而抗体发现的高吞吐量方法具有 通过产生关键的诊断生物标志物来改变自身免疫性神经病学领域，T细胞AGS仍然存在 鉴于缺乏高吞吐量T细胞AG发现平台，在很大程度上不确定。这个知识差距是 鉴于T细胞在疾病发病机理中起重要作用，因此很重要。当前的提议引入了 新技术，以解决同时评估许多候选人AG的挑战 T细胞库，该曲目基于一个工程生物传感器，该生物传感器检测到免疫突触的形成 单细胞水平，允许多路复用分析。该提案概述了第一个进一步发展的实验 免疫突触传感技术用于自身免疫T细胞中AG发现的目的。 指导和培训：我的培训将通过正式课程和直接完成 Wendell Lim，博士学位包括世界领导人的指导，在合成生物学和 细胞工程技术。 Lim教授在UCSF的20年中指导了大约50个博士后研究员 以及5个临床研究员。我将由医学博士/博士学位的斯科特·扎姆维尔（Scott Zamvil 医师科学家在神经免疫学和自身免疫性抗原生物学方面拥有丰富的经验。 环境：旧金山加利福尼亚大学是一个杰出的研究环境， 艺术设施和世界知名的教职员工。作为UCSF神经病学系的成员 神经免疫学和神经胶质生物学以及UCSF细胞设计学院，我的工作和培训将桥接 合成细胞工程和自身免疫性AG发现。我将从现有的临床自动抗原中受益 威尔逊博士领导的发现基础设施，包括UCSF脑炎和脑膜炎中心。