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

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细胞中调节机制的丧失介导的。超过50种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Manjarrez-Ordu ú o博士K 01奖项申请的修订版，旨在帮助她转变为独立研究者，能够根据对遗传功能后果的理解，为系统性狼疮中失调的分子相互作用提出治疗靶点。变异在B细胞中。该提案将为Manjaliz-Ordu o博士提供以下方面的培训：（1）遗传学和基因组学，（2）统计方法，和（3）B细胞生物学。这些目标的实现将通过由贝蒂钻石博士领导的跨学科指导来完成，贝蒂钻石博士将提供自身免疫性疾病和B细胞生物学方面的专业知识，彼得K。他将负责遗传学和生物网络分析方面的培训。本研究的目的是了解在B细胞成熟和活化过程中，Csk如何通过调节B细胞受体（BCR）来控制抗体应答。具体来说，我们将确定是否Csk介导的调节B细胞信号扰动条件的发展过程中的耐受性成熟的过渡细胞（目标1），下一步，我们将集中在幼稚B细胞产生的证据表明，较高的Csk表达导致BCR高反应性介导的CD 22和FcR？IIb（目标2），最后我们将证明这两个事件收敛于自身反应性库（目标3）的产生，为自身免疫性疾病的发展创造条件。因为这个项目的重点是人类细胞中发生的事件，它将产生可直接转化为人类疾病和治疗的知识。所产生的数据应允许Manjelz-Ordu o博士在培训期结束前竞争R 01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.