CSK polymorphisms, B cell signaling and autoreactivity of the human B cell repert

CSK 多态性、B 细胞信号转导和人类 B 细胞反应的自身反应性

基本信息

批准号：
8581566
负责人：
Nataly Manjarrez-Orduno
金额：
$ 12.77万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581566
关键词：
Achievement Affect Alleles Antibodies Antibody Formation Antigens Apoptosis Autoantigens Autoimmune Diseases Autoimmunity B cell repertoire B-Cell Activation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Binding Biological CD22 gene CD80 gene Cell Differentiation process Cell Maturation Cell Proliferation Cell physiology Cells Cellular biology Code Complex Data Development Diamond Disease Disease susceptibility Event Flow Cytometry Frequencies Funding Generations Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype Goals Haplotypes Human Hyperactive behavior IL2RA gene Immunoglobulin-Secreting Cells Immunoglobulins Knowledge Lead Life Lupus Lupus Erythematosus Mature B-Lymphocyte Measures Mediating Mentored Research Scientist Development Award Mentorship Modeling Modification Nuclear Antigens Nucleic Acid Regulatory Sequences PTPN22 gene Pathology Pathway Analysis Pathway interactions Pattern Peripheral Phenotype Phosphorylation Plasma Cells Play Process Proteins Protocols documentation Receptor Signaling Receptors, Antigen, B-Cell Regulation Regulatory Pathway Research Personnel Risk Role Signal Pathway Signal Transduction Staging Statistical Methods Surface Systemic Lupus Erythematosus Testing Tissues Training Transitional Cell Umbilical Cord Blood Variant Woman anti-IgM autoreactive B cell autoreactivity base career crosslink design genetic variant human disease protein-tyrosine kinase c-src public health relevance receptor release of sequestered calcium ion into cytoplasm risk variant src-Family Kinases systemic autoimmune disease therapeutic target young woman

项目摘要

DESCRIPTION (provided by applicant): Lupus erythematosus is a disease that affects primarily young women. Its pathology is mediated to a large extent by the loss of regulatory mechanisms in B cells. More than 50 gene polymorphisms have been associated with increased risk for systemic lupus, many of them related to B cell function, but the mechanisms by which these variants increase disease susceptibility is still unknown. This is a revision for an application for a K01 award for Dr. Manjarrez-Ordu¿o designed to help her make the transition to an independent investigator, able to propose therapeutic targets for deregulated molecular interactions in systemic lupus based on an understanding of the functional consequences of genetic variation in B cells. This proposal will provide Dr. Manjarrez-Ordu¿o with training in (1) genetics and genomics, (2) statistical methods, and (3) B cell biology. The achievement of these goals will be accomplished with cross-disciplinary mentorship led by Dr. Betty Diamond who will provide with expertise on autoimmune diseases and B cell biology, and Dr. Peter K. Gregersen who will manage the training in genetics and biological network analysis. The aim of this proposal is to understand how Csk controls antibody responses by its regulation of the B cell receptor (BCR) both during B cell maturation and activation. Specifically, we will determine whether Csk-mediated regulation of the B cell signaling perturbs the conditions for the development of tolerance during maturation of transitional cells (Aim 1); next, we will focus on na¿ve B cells to generate evidence that higher Csk expression leads to BCR hyper-responsiveness mediated by CD22 and FcR?IIb (Aim 2) and finally we will prove that these two events converge in the generation of an autoreactive repertoire (Aim 3), setting the conditions for the development of autoimmune disease. Because this project focuses on events that happen in human cells, it will generate knowledge that is directly translatable into human disease and therapy. The data generated should allow Dr. Manjarrez- Ordu¿o to compete for R01 funding before the end of this training period.

描述（由申请人提供）：红斑狼疮是一种主要影响年轻女性的疾病，其病理学在很大程度上是由 B 细胞调节机制的丧失介导的，超过 50 个基因多态性与系统性狼疮风险增加有关。其中许多与 B 细胞功能有关，但这些变异增加疾病易感性的机制仍不清楚。这是对 Dr. K01 奖申请的修订。曼贾雷斯-奥尔杜¿ o 旨在帮助她转型为独立研究者，能够根据对 B 细胞遗传变异功能后果的理解，提出系统性狼疮中分子相互作用失调的治疗目标。该建议将为 Manjarrez-Ordu 博士提供帮助。 o 接受 (1) 遗传学和基因组学、(2) 统计方法和 (3) B 细胞生物学方面的培训这些目标的实现将通过 Betty Diamond 博士领导的跨学科指导来实现，她将提供相关专业知识。自身免疫性疾病和 B 细胞生物学，以及 Peter K. Gregersen 博士将管理遗传学和生物网络分析方面的培训。该提案的目的是了解 Csk 如何通过调节 B 细胞受体 (BCR) 来控制抗体反应。 B 细胞成熟期间和具体来说，我们将确定 Csk 介导的 B 细胞信号传导调节是否会扰乱过渡细胞成熟过程中耐受性发展的条件（目标 1）；接下来，我们将重点关注 na¿ ve B 细胞产生证据表明较高的 Csk 表达导致由 CD22 和 FcR?IIb 介导的 BCR 高反应性（目标 2），最后我们将证明这两个事件汇聚在自身反应性指令集的生成中（目标 3），设置由于该项目专注于人类细胞中发生的事件，因此它将产生可直接转化为人类疾病和治疗的知识。应该允许 Manjarrez-Ordu 博士o 在此培训期结束前争夺 R01 资金。