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

描述(申请人提供)：红斑狼疮是一种主要影响年轻女性的疾病。其病理机制在很大程度上是由B细胞调节机制的丧失所介导的。超过50个基因多态性与系统性红斑狼疮的风险增加有关，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Manjarrez-Orduo博士K01奖申请的修订，该奖项旨在帮助她过渡到一名独立的研究人员，能够根据对B细胞遗传变异的功能后果的理解，为系统性狼疮的放松管制的分子相互作用提出治疗靶点。这项建议将为Manjarrez-Orduéo博士提供(1)遗传学和基因组学、(2)统计学方法和(3)B细胞生物学方面的培训。这些目标的实现将在贝蒂·戴蒙德博士和彼得·K·格雷格森博士领导的跨学科指导下实现，贝蒂·戴蒙德博士将提供自身免疫疾病和B细胞生物学方面的专业知识，彼得·K·格雷格森博士将管理遗传学和生物网络分析方面的培训。这项建议的目的是了解CSK是如何通过调节B细胞成熟和激活期间的B细胞受体(BCR)来控制抗体反应的。具体地说，我们将确定CSK介导的B细胞信号调节是否扰乱了过渡细胞成熟期间耐受发展的条件(目标1)；接下来，我们将专注于NA？B细胞，以产生证据表明更高的CSK表达导致CD22和FCR？IIB介导的BCR高反应(目标2)，最后我们将证明这两个事件在产生自身反应的过程中汇聚(目标3)，为自身免疫病的发展设定条件。因为这个项目专注于人类细胞中发生的事件，所以它将产生可直接转化为人类疾病和治疗的知识。生成的数据将使Manjarrez-Orduéo博士能够在本次培训结束前争取R01资金。

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.