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。其病理在很大程度上是由B细胞调节机制的缺失介导的。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。这是对manjarez - ordu¿o博士申请K01奖的修订，旨在帮助她过渡到独立研究者，能够基于对B细胞遗传变异的功能后果的理解，提出系统性狼疮中不受管制的分子相互作用的治疗靶点。该提案将为manjarez - 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，(3)B细胞生物学。这些目标的实现将在Betty Diamond博士和Peter K. Gregersen博士的跨学科指导下完成，Betty Diamond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，Peter K. Gregersen博士将管理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细胞成熟和激活过程中，Csk是如何通过调节B细胞受体（BCR）来控制抗体反应的。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干扰移行细胞成熟过程中耐受性发育的条件（Aim 1）；接下来，我们将重点关注na - ve B细胞，以提供证据证明高Csk表达导致CD22和FcR介导的BCR高反应性。IIb（目的2），最后我们将证明这两个事件在自身反应库的产生（目的3）中汇合，为自身免疫性疾病的发展创造条件。由于该项目关注的是发生在人体细胞中的事件，因此它将产生可直接转化为人类疾病和治疗的知识。生成的数据应允许manjararez - Ordu¿o博士在培训期结束前竞争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.