Regulation of antibody secreting cell (ASC) homeostasis by Ufbp1.

Ufbp1 对抗体分泌细胞 (ASC) 稳态的调节。

基本信息

批准号：
10099811
负责人：
Nagendra Singh
金额：
$ 46.2万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-24 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10099811
关键词：
Affect Antibodies Antibody Affinity Antibody Response Antigens Apoptosis Arginine B cell differentiation B-Cell Activation B-Lymphocytes Binding Proteins Bone Marrow Cell Line Cell Lineage Cell Maintenance Cell Survival Cellular biology Complex Data Development Disease Endoplasmic Reticulum Enzymes Event Generations Genetic Home environment Homeostasis Immune response Immunoglobulin-Secreting Cells Immunoglobulins Impairment Infection Knowledge Life Lysine Mediating Mitochondria Molecular Mus Oils Outcome Pathology Pathway interactions Pharmacology Phosphotransferases Physiological Plasma Cells Plasmablast Play Process Proteins Publishing Rag1 Mouse Reaction Regulation Role Serum Site Structure Tamoxifen Testing Therapeutic Ubiquitin Vaccination Vaccines base cofactor design knock-down mutant novel pathogen polypeptide response secondary lymphoid organ self-renewal ubiquitin-protein ligase

Affect Antibodies Antibody Affinity Antibody Response Antigens Apoptosis Arginine B cell differentiation B-Cell Activation B-Lymphocytes Binding Proteins Bone Marrow Cell Line Cell Lineage Cell Maintenance Cell Survival Cellular biology Complex Data Development Disease Endoplasmic Reticulum Enzymes Event Generations Genetic Home environment Homeostasis Immune response Immunoglobulin-Secreting Cells Immunoglobulins Impairment Infection Knowledge Life Lysine Mediating Mitochondria Molecular Mus Oils Outcome Pathology Pathway interactions Pharmacology Phosphotransferases Physiological Plasma Cells Plasmablast Play Process Proteins Publishing Rag1 Mouse Reaction Regulation Role Serum Site Structure Tamoxifen Testing Therapeutic Ubiquitin Vaccination Vaccines base cofactor design knock-down mutant novel pathogen polypeptide response secondary lymphoid organ self-renewal ubiquitin-protein ligase

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项目摘要

Secreted antibodies play an important role in the neutralization of pathogens and the protection of host. Two types of ASCs develop during B cell responses: short lived plasmablasts (PBs) and long-lived plasma cells (PCs). In secondary lymphoid organs, antigen-activated B cells differentiate into PBs. Some of these PBs home to bone marrow, where they differentiate into long-lived PCs. In bone marrow, PCs persist from a few months to years and secrete copious amounts of high-affinity antibodies which are central to the neutralization of pathogens. Therefore, understanding the molecular mechanisms underlying the development, survival and function of plasma cells is critical to designing better vaccines to generate effective immune responses. Ufm1 (ubiquitin-fold modifier 1) is a ubiquitin-like polypeptide that is post- translationally conjugated to target proteins via the ufmylation process and thereby modifies their function. Ufm1 binding protein (Ufbp1 or DDGRK1) is the first identified target of the ufmylation pathway. Ufl1 is the E3 ligase that attaches Ufm1 to Ufbp1. We published a novel role of Ufbp1 in development and function of ASCs. Consistent with this, mice lacking Ufbp1 in B cells have significantly reduced amounts of serum immunoglobulins and mount a highly defective antibody response against antigens. Aim 1 will use structure-function analysis to identify the regions of Ufbp1 that differentially regulate development of ASC and helps them to acquire the ability to produce antibodies. Aim 2 will test the roles of Ufm1 and Ufl1 pathway in development and function of ASCs. Aim3 will test the role of Ufbp1, Ufl1 and Ufm1 in promoting survival of long-lived PCs, maintaining their functionality and underlying molecular mechanisms. The outcome of the proposed study will provide an understanding of a novel molecular mechanism underlying Ufbp1-mediated promotion of antibody response and could potentially help in designing better vaccines and treatments for pathologies related to antibody secreting cells.

分泌的抗体在中和病原体和宿主的保护中起着重要作用。在B细胞反应期间出现了两种类型的ASC：短寿命的血浆（PBS）和长寿命等离子体细胞（PC）。在继发性淋巴器官中，抗原激活的B细胞分化为PBS。其中一些 PBS的骨髓所在地，它们分为长寿命PC。在骨髓中，PC持续几个月到几年，分泌大量的高亲和力抗体，这是病原体中和。因此，了解依据的分子机制浆细胞的开发，生存和功能对于设计更好的疫苗至关重要有效的免疫反应。 UFM1（泛素折叠式修饰剂1）是一种泛素样的多肽，是翻译通过ufmylation过程将靶蛋白结合在一起，从而修改其功能。 UFM1结合蛋白（UFBP1或DDGRK1）是UFMylation途径的第一个识别靶标。 UFL1是将UFM1连接到UFBP1的E3连接酶。我们发表了UFBP1在开发和功能中的新作用 ASC。与此一致，B细胞中缺乏UFBP1的小鼠的血清量显着降低免疫球蛋白并对针对抗原产生高度缺陷的抗体反应。 AIM 1将使用结构功能分析以识别UFBP1区域的区域，以差异调节ASC的发展并帮助他们获得产生抗体的能力。 AIM 2将测试UFM1和UFL1的角色 ASC的发展和功能的途径。 AIM3将测试UFBP1，UFL1和UFM1在促进中的作用长寿命PC的存活，维持其功能和潜在的分子机制。这拟议研究的结果将提供对一种新的分子机制的理解 UFBP1介导的抗体反应促进，并有可能有助于设计更好的疫苗以及与抗体分泌细胞有关的病理治疗。