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

基本信息

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
项目类别：
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

项目摘要

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- 基于的研究项目专注于自身免疫性神经系统疾病中的 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）来自一支经验丰富的团队的指导科学家和医师科学家，（2）致力于教学以扩展我的基础和临床知识免疫学和合成生物学 (3) 生物传感器工程和 T 细胞 Ag 方面的广泛实践培训检测，以及 (4) R01 应用程序的数据收集。研究：T 细胞是导致自身免疫性神经系统疾病（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开发更精确的相对于基础广泛的疗法，有望提高疗效和更好的安全性目前使用的免疫抑制剂。虽然抗体发现的高通量方法已经通过产生关键的诊断生物标志物，T 细胞抗原改变了自身免疫神经学领域由于缺乏高通量 T 细胞 Ag 发现平台，很大程度上未定义。这种知识差距是鉴于 T 细胞在疾病发病机制中发挥重要作用，这一点意义重大。目前的提案引入了新技术来解决同时评估许多候选Ags与不同的Ags的挑战 T 细胞库，基于工程生物传感器，可检测免疫突触的形成单细胞水平，允许多重分析。该提案概述了进一步开发的第一个实验用于在自身免疫 T 细胞中发现 Ag 的免疫突触传感技术。指导和培训：我的培训将通过正式课程并在直接指导下完成世界领导人的指导，包括 Wendell Lim 博士，他在合成生物学和细胞工程技术。 Lim 教授在 UCSF 工作了 20 多年，指导了约 50 名博士后研究员以及5名临床研究员。我将得到医学博士/博士 Scott Zamvil 和 MAS 医学博士 Michael Wilson 的共同指导在神经免疫学和自身免疫抗原生物学方面拥有丰富经验的医师科学家。环境：加州大学旧金山分校拥有卓越的研究环境，最先进的设施和世界知名的师资队伍。作为 UCSF 神经科的成员神经免疫学和神经胶质生物学以及加州大学旧金山分校细胞设计研究所，我的工作和培训将架起桥梁合成细胞工程和自身免疫抗原的发现。我将从现有的临床自身抗原中受益发现基础设施，包括由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。