The Molecular Mechanism of the CD19-CD81 B Cell Co-Receptor Complex

CD19-CD81 B细胞共受体复合物的分子机制

基本信息

批准号：
10245154
负责人：
Katherine Julia Susa
金额：
$ 2.85万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245154
关键词：
Antigens Auditory system Autoimmunity Award B lymphoid malignancy B-Cell Activation B-Cell Antigen Receptor B-Cell Development B-Lymphocytes Binding Biochemical Bioethics Biological Assay Cardiovascular system Cell physiology Cell surface Cells Cellular biology Communicable Diseases Complex Coupled Cryoelectron Microscopy Crystallography Data Defect Deuterium Development Disease Drug Targeting Experimental Designs Fellowship Flow Cytometry Foundations Future Goals Graduate Education Health Human Hydrogen Immune response Immune system Immunologic Deficiency Syndromes Inflammation Integral Membrane Protein Investigation Knowledge Label Lead Lipids Maintenance Mass Spectrum Analysis Measures Mediating Membrane Membrane Microdomains Membrane Proteins Mentorship Molecular Molecular Chaperones Molecular Conformation Neoplasm Metastasis Nervous system structure Null Lymphocytes Pathway interactions Peroxidases Phase Physiology Play Process Production Protein Biochemistry Proteins Public Speaking Receptor Signaling Regulation Reproductive system Research Research Personnel Role Signal Pathway Signal Transduction Structure Surface Training Writing ascorbate assay development base body system design drug development experimental study insight medical schools meetings member mutant novel novel therapeutics organ growth protein transport receptor scaffold structural biology trafficking tumor

项目摘要

Abstract The tetraspanins comprise a class of four-pass transmembrane proteins that have acquired a variety of discrete, yet poorly understood, functions in mammalian physiology, playing essential roles in the immune, nervous, cardiovascular, reproductive, and auditory systems, as well as in infectious disease processes, tumor metastasis, and the development of organ systems. The functions of tetraspanins are mediated through their direct interaction with partner proteins, and one of the most critical functions of a tetraspanin is the regulation of B cell signaling via the interaction between the tetraspanin cluster of differentiation 81 (CD81) and the B cell co-receptor, cluster of differentiation 19 (CD19). Altered expression and signaling of CD19 causes defects in B cell development and has been implicated in the development of immunodeficiency, B cell malignancies, and autoimmunity. However, the mechanism by which CD81 regulates the trafficking and signaling of CD19 is unclear, largely due to a lack of structural and biochemical data. Therefore, I propose to investigate the molecular mechanism of tetraspanin regulation of CD19 through: i) structural characterization of the CD19- CD81 complex, and ii) functional studies of CD19 trafficking to the cell surface and signaling after B cell activation in cell-based assays. A better understanding of the molecular mechanism underlying CD19-CD81 function will have broad biomedical implications, offering novel insights into B cell biology and signal transduction mechanisms, tetraspanin function, and how to better target the B cell signaling pathway for novel therapeutics. Under the F31 fellowship award, I will receive exceptional training in structural biology, membrane protein biochemistry, and assay development under the guidance of Dr. Kruse and Dr. Blacklow at Harvard Medical School. My technical training will be accompanied by training in experimental design, mentorship, public speaking, biomedical ethics, scientific writing, and opportunities to present my research at scientific meetings. This training plan is designed to lead to a successful and productive graduate education and will provide an outstanding foundation for achieving my long-term goal of becoming an independent researcher focused on transmembrane signaling.

抽象的四跨膜蛋白包含一类四次跨膜蛋白，已获得多种在哺乳动物生理学中，离散但知之甚少的功能，在免疫、神经、心血管、生殖和听觉系统，以及传染病过程、肿瘤转移和器官系统的发育。四跨膜蛋白的功能是通过其介导的与伴侣蛋白直接相互作用，四跨膜蛋白最关键的功能之一是调节通过四跨膜蛋白分化簇 81 (CD81) 和 B 细胞之间的相互作用进行 B 细胞信号传导辅助受体，分化簇 19 (CD19)。 CD19 表达和信号传导的改变导致 B 细胞缺陷细胞发育，并与免疫缺陷、B 细胞恶性肿瘤和自身免疫。然而，CD81 调节 CD19 的运输和信号转导的机制是不清楚，主要是由于缺乏结构和生化数据。因此，我建议调查四跨膜蛋白通过以下方式调节 CD19 的分子机制： i) CD19-的结构表征 CD81 复合物，以及 ii) CD19 运输到细胞表面和 B 细胞后信号传导的功能研究基于细胞的测定中的激活。更好地了解 CD19-CD81 的分子机制功能将具有广泛的生物医学意义，为 B 细胞生物学和信号提供新的见解转导机制、四跨膜蛋白功能以及如何更好地靶向 B 细胞信号通路以开发新的疗法。根据 F31 奖学金，我将接受结构生物学、膜蛋白方面的特殊培训在哈佛医学院 Kruse 博士和 Blacklow 博士的指导下进行生物化学和检测开发学校。我的技术培训将伴随着实验设计、指导、公共培训等方面的培训演讲、生物医学伦理、科学写作以及在科学会议上展示我的研究的机会。该培训计划旨在实现成功且富有成效的研究生教育，并将提供为实现我成为一名独立研究员的长期目标奠定了良好的基础跨膜信号传导。