Expression of BTB-ZF Transcriptional Regulators as Biomarkers of Immune System Development

 描述(由申请人提供)：BTB/POZ-ZF[BRoad Complex，TramTrack，Bric a‘brac(BTB)或痘病毒和锌指(POZ)-锌指]是一个转录调控蛋白家族。这些BTB-锌指(BTB-ZF)家族成员由N端蛋白质-蛋白质相互作用结构域(BTB/POZ)和C端锌指结构域的存在所定义。这个家族的成员已经成为基本的、非多余的因素，控制着几种不同类型的免疫系统细胞的发育或功能。例如，BTB-ZF基因已被证明控制T细胞对B细胞的承诺(LRF)，CD4对CD8谱系的承诺(ThPOK和MAZR)，胸腺细胞对天然T细胞谱系的承诺(PLZF)，以及生发中心B细胞的发育(Bcl6)。重要的是，这些基因并不是普遍表达的。事实上，即使是关系非常密切的细胞也不表达相同的基因。例如，在γδT细胞中，PLZF仅在Vγ1.1Vδ6.3TCR的T细胞中表达。ThPOK在CD4T细胞中表达，但在CD8T细胞中不表达。因此，BTB-ZF基因家族的表达受到严格的调控，但当表达时，这些基因控制着细胞发育和/或功能的基本方面。我们推测，在单细胞水平上了解BTB-ZF基因家族在淋巴细胞中的表达谱将提供 免疫系统的一种特征，可用作免疫系统功能的生物标志物。每个BTB-ZF基因成员都有可能控制不同和特定的细胞亚群的功能或命运。因此，了解这个基因家族将对我们理解免疫反应的整体复杂性产生深远的影响。这些见解有望对疫苗开发、癌症治疗和自身免疫性疾病的管理产生重要影响。与RWJMS的新生儿科合作，我们建议开发高通量分析方法，在单细胞水平上定义离散淋巴细胞群体中BTB-ZF的表达模式。从足月、剖宫产中分离的脐带血淋巴细胞将用于新生儿之间的比较以及与成人外周血淋巴细胞的比较。通过这种方法，我们将在出生时定义一个“基线”转录因子谱，使我们能够描述成年人口中发生的变化。我们建议，这些数据将使我们能够探索疾病背景下的可量化变化。总体而言，我们预计这些数据将提供一种新的、强大的新手段来询问人类免疫系统的完整性。

 DESCRIPTION (provided by applicant): The BTB/POZ-ZF [Broad complex, Tramtrack, Bric a`brac (BTB) or poxvirus and zinc finger (POZ)-zinc finger] is a protein family of transcriptional regulators. These BTB-zinc finger (BTB-ZF) family members are defined by the presence of an N-terminal protein-protein interaction domain (BTB/POZ) and C-terminal zinc finger domains. Members of this family have emerged as fundamental, non-redundant factors that control the development or function of several different cell types of the immune system. BTB-ZF genes have, for example, been shown to control T cell versus B cell commitment (LRF), CD4 versus CD8 lineage commitment (ThPOK and MAZR), commitment of thymocytes to innate T cell lineages (PLZF), and development of germinal center B cells (Bcl6). Importantly, these genes are not ubiquitously expressed. Indeed, even very closely related cells do not express the same genes. For example, PLZF was found to be expressed in NKT cells, but never in non-innate T cells, B cells, eosinophils, etc. Among γδ T cells, PLZF is only expressed in those with the Vγ1.1Vδ6.3 TCR. ThPOK is expressed in CD4 T cells, but not CD8 T cells. Expression of the BTB-ZF gene family, therefore, is tightly regulated, but when expressed, these genes control fundamental aspects of cell development and/or function. We hypothesize that understanding the expression profile of the BTB-ZF gene family in lymphocytes at the single cell level will offer a profile of the immune system that can be used as a biomarker for immune system function. Each BTB-ZF gene member has the potential to control the function or fate of distinct and specific cellular subsets. Therefore, understanding this gene family will have a profound impact on our understanding of the overall complexity of the immune response. These insights are expected to have important implications for vaccine development, cancer treatment and the management of autoimmune diseases. Working with our neonatology department at RWJMS, we propose to develop high throughput assays to define BTB-ZF expression patterns in discrete populations of lymphocytes at the level of the single cell. Cord blood lymphocytes isolated from full term, Caesarian births will be used for comparison among newborns and for comparison to adult peripheral blood lymphocytes. By this approach, we will define a "baseline" transcription factor profile at birth enabling us to characterize changes that occur in the adult population. We propose that these data, we will enable us to explore quantifiable changes in disease settings. Overall, we anticipate that these data will provide a novel and powerful new means to interrogate the integrity of the human immune system.