Targeting B lymphocyte Signaling to Reprogram Autoimmunity in Type 1 Diabetes

 描述（由申请人提供）：本提案中的培训平台侧重于B淋巴细胞中的细胞内信号传导，作为纠正免疫耐受中的基本缺陷和监测治疗干预以重新编程胰岛破坏性免疫的新方法。虽然许多工作已经进入理解驱动T1 D的细胞间过程，但控制对胰岛抗原的破坏性反应的细胞内级联反应尚未确定。自身抗体的产生是最早可用的自身免疫生物标志物，但允许这种免疫耐受破坏的机制仍然未知。虽然利妥昔单抗靶向整个B淋巴细胞池延迟了新发T1 D的进展，但该效应是短暂的，这可能与长期重编程胰岛反应细胞失败有关。像T细胞一样，B细胞经历多个发育阶段，在此期间，它们通过抗原接触被编程为对自身抗原耐受。这个程序在T1 D中失败了，我假设这是由于B细胞发育过程中抗原接触和效应子反应之间的不正确偶联。在我的初步研究中，我利用尖端的磷酸化流式细胞术的新方法来揭示NOD小鼠的过渡1（T1）B淋巴细胞亚群中c-Abl信号传导的缺陷，这是T1 D的基准临床前模型。虽然c-Abl在肿瘤发生中的功能已被广泛剖析，但其在B细胞中免疫耐受编程中的作用在很大程度上是未知的。在这个建议中，我将剖析的c-Abl依赖的信号通路，管理B淋巴细胞耐受机制。我推测，c-Abl调节稳态扩张和负选择之间的平衡，在过渡B淋巴细胞隔室和缺陷，在这一途径的基础B淋巴细胞选择缺陷的自身免疫性疾病。我将剖析c-Abl介导的途径，控制B淋巴细胞的稳态和选择，通过应用转基因，抗原特异性系统和治疗靶向的c-Abl途径的疾病调制（目标1）。我将扩展这种免疫信号的分析，以了解免疫功能是如何在疾病修饰治疗过程中使用信息学方法结合高维质谱细胞术（Aim 2）重新编程的。通过这项奖学金申请，我将开发1）在耐受诱导过程中B细胞调节的新的细胞内途径的详细了解和2）我的潜力作为一个基础和翻译科学家专注于T1 D。这些培训目标将通过研究计划、具有拟定研究设计专业知识的杰出导师团队、完成霍华德休斯分子医学证书课程以及范德比尔特大学提供的资源、设施和培训计划来实现。

 DESCRIPTION (provided by applicant): The training platform in this proposal focuses on intracellular signaling in B lymphocytes as a new approach to correcting fundamental defects in immune tolerance and to monitoring therapeutic interventions to reprogram islet-destructive immunity. While much work has gone into understanding the intercellular processes that drive T1D, the intracellular cascades that control the destructive responses to islet antigens are undefined. The production of autoantibodies is the earliest available biomarker of autoimmunity, but the mechanisms that permit this breach in immune tolerance remain unknown. While targeting of the whole B lymphocyte pool with rituximab delayed the progression of new-onset T1D, the effect was transient, which may relate to failure to reprogram islet-reactive cells long-term. Like T cells, B cells progress through multiple developmental stages during which they are programmed by antigen contact to be tolerant to self-antigens. This program fails in T1D, which I have hypothesized is due to improper coupling between antigen contact and effector responses during B cell development. In my preliminary studies, I have utilized new approaches in cutting-edge, phosphoflow cytometry to uncover defects in c-Abl signaling in the Transitional 1 (T1) B lymphocyte subset of NOD mice, the benchmark preclinical model of T1D. While the function of c-Abl in oncogenesis has been extensively dissected, its role in the programming of immune tolerance in B cells is largely unknown. In this proposal I will dissect the c-Abl dependent signaling pathways that govern B lymphocyte tolerance mechanisms. I hypothesize that c-Abl modulates the balance between homeostatic expansion and negative selection in the transitional B lymphocyte compartment and that defects in this pathway underlie B lymphocyte selection defects found in autoimmune disease. I will dissect c-Abl mediated pathways that control B lymphocyte homeostasis and selection by applying transgenic, antigen-specific systems and therapeutic targeting of c-Abl pathways for disease modulation (Aim 1). I will extend this analysis of immune signaling to understand how immune function is reprogrammed during disease-modifying therapy using informatics approaches combined with high dimensional mass cytometry (Aim 2). Through this fellowship application, I will develop 1) a detailed understanding of new intracellular pathways of B cell regulation during tolerance induction and 2) my potential as a basic and translational scientist focused on T1D. These training goals will be facilitated by the research plan, by the exceptional team of mentors with expertise in the proposed study design, by completion of the Howard Hughes Certificate Program in Molecular Medicine, and by the resources, facilities, and training plan available through Vanderbilt University.