MR1-dependent presentation of Mycobacterium tuberculosis: a unique role for calcium signaling

结核分枝杆菌的 MR1 依赖性表达：钙信号传导的独特作用

• 批准号: 10415103
• 负责人: Elham Karamooz
• 金额: $ 18.55万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415103
• 关键词: Adopted; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Award; Basic Science; Binding; Biometry; Calcium; Calcium Channel; Calcium Signaling; Cell membrane; Cell surface; Cells; Collaborations; Communicable Diseases; Data; Detection; Development; Development Plans; Disease; Environment; Fluorescence Microscopy; Future; Glycolipids; Goals; Health Sciences; Histocompatibility Antigens Class II; Human; Immune system; Immunology; Immunotherapy; Infection; Institution; Knowledge; Lead; Ligands; Lipids; Lung; Masks; Measurement; Measures; Mentors; Metabolism; Microbe; Modeling; Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Oregon; Peptides; Positioning Attribute; Process; Recycling; Research; Resistance; Role; Sampling; Scientist; Signal Transduction; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Tissues; Training; Tuberculosis; Universities; Work; Writing; arm; base; calcium indicator; career development; clinically relevant; experience; immune system function; innovation; interest; knock-down; live cell imaging; microbial; mortality; novel; pathogen; protein transport; skills; small molecule; symposium; synaptotagmin; syntaxin 16; trafficking

Project Summary The fundamental role of the immune system is to detect self from non-self. The detection and elimination of microbial infection is critical for human survival. One challenge to the immune system is infection from an intracellular microbe because the microbe masks its presence in a host cell. One strategy of the immune system to detect microbes is the sampling of different kinds of antigens, such as peptides, lipids and glycolipids, by antigen presenting molecules. A fundamentally unique arm of the immune system is MR1, which is an antigen presenting molecule that is intracellular, ubiquitously expressed across tissues, and detects small molecules derived from microbial metabolism. These features suggest that MR1 is poised to detect intracellular microbes. MR1 presents antigens to MR1-restricted T cells. These T cells are highly prevalent in the lungs and have the ability to kill infected cells. Because MR1 presents small molecule antigens and adopts an intracellular distribution, the mechanisms governing MR1 sampling of the intracellular environment are distinct from other antigen presenting molecules. Our hypothesis is that endosomal recycling and endosomal calcium signaling are key for MR1-dependent antigen presentation, and that these features distinguish MR1 from MHC- Ia antigen presentation. We use Mycobacterium tuberculosis (Mtb) as a model for intracellular infection and have identified calcium-sensitive trafficking proteins and calcium channels important for MR1 antigen presentation. In Aim 1, we will define the role of the endosomal trafficking protein Syntaxin 16 in MR1- dependent antigen presentation. In Aim 2, we will define the role of calcium sensitive Synaptotagmins in MR1- dependent antigen presentation. In Aim 3, we will identify the important calcium channels involved in this process and examined the role of Two-pore channels. This research plan is part of a detailed training and career development plan for the applicant. In addition to hands-on basic science research with an emphasis on techniques such as measurement of intracellular calcium and live-cell fluorescence microscopy, the applicant will complete coursework in scientific writing and biostatistics to expand scientific knowledge and will attend scientific conferences to develop collaborations. Acquisition of all of these skills will lead to expertise in defining intracellular signaling cascades in antigen presenting cells, with the goal of obtaining an R01 by the end of the K08 award. The primary mentor has a long track record of training scientists and a Mentoring Committee will track the applicant's progress and contribute to the applicant's development as a scientist. Finally, the sponsoring institution, Oregon Health & Science University, has all the facilities and support necessary to support the proposal.

项目摘要 免疫系统的基本作用是从非自我中检测自我。检测和消除 微生物感染对于人类生存至关重要。免疫系统的一个挑战是感染 细胞内微生物是因为微生物掩盖了其在宿主细胞中的存在。免疫的一种策略 检测微生物的系统是对不同种类的抗原的取样，例如肽，脂质和 通过抗原呈现分子的糖脂。免疫系统的根本独特部门是MR1，它 是一种抗原呈现细胞内的抗原分子 源自微生物代谢的分子。这些功能表明MR1准备检测细胞内 微生物。 MR1向MR1限制的T细胞提供抗原。这些T细胞在肺中高度普遍， 具有杀死感染细胞的能力。因为MR1呈现小分子抗原并采用 细胞内分布，管理细胞内环境MR1采样的机制是不同的 来自其他抗原呈现分子。我们的假设是内体回收和内体钙 信号传导是MR1依赖性抗原表现的关键，并且这些特征将MR1与MHC-区分开 IA抗原表现。我们使用结核分枝杆菌（MTB）作为细胞内感染和 已经鉴定出对钙敏感的运输蛋白和钙通道对MR1抗原很重要 推介会。在AIM 1中，我们将定义内体贩运蛋白语法16在MR1-中的作用。 依赖性抗原表现。在AIM 2中，我们将定义钙敏感突触毒素在MR1-中的作用。 依赖性抗原表现。在AIM 3中，我们将确定其中涉及的重要钙通道 过程并检查了两孔通道的作用。该研究计划是详细培训的一部分， 申请人的职业发展计划。除了动手基础科学研究之外 诸如细胞内钙和活细胞荧光显微镜的测量，申请人 将完成科学写作和生物统计学的课程，以扩大科学知识，并将参加 科学会议开发合作。获取所有这些技能将导致定义的专业知识 细胞内信号传导在抗原呈递细胞中的层流，目的是在末尾获得R01 K08奖。主要导师的培训科学家有很长的记录，指导委员会将 跟踪申请人的进步，并为申请人作为科学家的发展做出贡献。最后， 赞助机构，俄勒冈州健康与科学大学，拥有所有必要的设施和支持 支持该提议。