Ikaros in mast vs. basophil lineage choice

描述(申请人提供)：直到最近，肥大细胞和嗜碱性粒细胞被认为是免疫系统中相当难懂的细胞，其主要作用是诱导过敏。然而，过去几年越来越多的证据表明，它们在免疫系统的启动和调节中发挥着关键作用。也很明显，这些细胞的不正常功能是慢性炎症和自身免疫性疾病，如多发性硬化症和类风湿性关节炎，甚至癌症的发病机制的核心。因此，了解这些细胞的个体发育和发育已成为当务之急。考虑到肥大细胞和嗜碱性粒细胞在几个方面是相似的，包括相对独特的高亲和力IgE受体的表达，并共享共同的激活、脱颗粒和介质释放模式，因此它们具有平行的发育途径也就不足为奇了。据报道，肥大细胞和嗜碱性粒细胞起源于一种常见的造血祖细胞--嗜碱粒细胞肥大细胞前体(BMCP)。然而，指导肥大细胞和嗜碱性细胞之间谱系选择的分子机制尚不清楚。粒细胞相关转录因子CCAAT/增强子结合蛋白1(C/EBP1)被报道将共同的前体导向嗜碱性粒细胞谱系。我们最近证实转录因子Ikaros调节肥大细胞IL-4基因的表达。此外，我们实验室的初步数据表明，Ikaros参与肥大细胞的发育，如果没有Ikaros，细胞默认为嗜碱性细胞系。在这个建议中，我们假设转录因子Ikaros驱动BMCP向肥大细胞谱系的谱系选择。正如在这些目标中所阐述的，我们将首先确定Ikaros是否以一种细胞固有的方式，使用Ikaros缺失的小鼠，以牺牲嗜碱性粒细胞为代价来调节对肥大细胞的谱系选择。其次，我们将确定Ikaros是否抑制嗜碱性粒细胞系促进C/EBP1等转录因子的表达。最后，我们将通过分析Ikaros缺失小鼠的嗜碱性粒细胞特异性反应来评估肥大发育中Ikaros缺失与嗜碱性粒细胞发育的体内相关性。这些实验的结果将进一步加深我们对肥大细胞和嗜碱性粒细胞之间的谱系选择决定的理解，并阐明炎性和自身免疫性疾病的潜在治疗靶点。 与公共卫生相关：造血系的所有细胞，包括红细胞、血小板和白细胞，都可以来自同一个前体干细胞。这种干细胞必须经历独特的发育步骤(谱系选择)，涉及特定基因的激活或抑制，以便正确地发育成我们血液系统的各种细胞类型。我们的研究集中在肥大细胞和嗜碱性粒细胞的发育上，这两种高度相关的细胞不仅是过敏症状的主要原因，而且对我们免疫系统的一些保护功能也是至关重要的：在这里，我们建议研究共同的前体细胞选择成为肥大细胞或嗜碱性细胞的机制。

DESCRIPTION (provided by applicant): Until recently, mast cells and basophils were considered to be rather obscure cells of the immune system whose main role is to induce allergy. However, increasing evidence over the last few years has illuminated their critical role in the initiation and regulation of the immune system. It has also become evident that improper functioning of these cells is central to the pathogenesis of chronic inflammatory and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and even cancer. Hence, understanding the ontogeny and development of these cells has become imperative. Considering the fact that mast cells and basophils are similar in several aspects including the relatively unique expression of the high affinity IgE receptor and share common modes of activation, degranulation and mediator release, it is not surprising that they have parallel developmental pathways as well. It has been reported that mast cells and basophils arise from a common hematopoietic precursor - the basophil-mast cell precursor (BMCP). However, the molecular mechanisms directing lineage choice between mast cell vs. basophil are unclear. The granulocyte-related transcription factor CCAAT/enhancer-binding protein 1 (C/EBP1) is reported to steer the common precursor towards the basophil lineage. We have recently demonstrated that the transcription factor Ikaros regulates mast cell IL-4 gene expression. Furthermore, preliminary data from our laboratory suggests that Ikaros is involved in mast cell development and without Ikaros, cells default to the basophil lineage. In this proposal we hypothesize that the transcription factor Ikaros drives the lineage choice of the BMCP towards mast cell lineage. As set forth in these aims, we will first determine whether Ikaros regulates lineage choice towards mast cells at the expense of basophils, in a cell intrinsic manner, using Ikaros-null mice. Secondly, we will determine whether Ikaros suppresses basophil lineage promoting transcription factors such as C/EBP1. Finally, we will assess the in vivo relevance of loss of Ikaros in mast vs. basophil development by analyzing basophil specific responses in Ikaros-null mice. Results obtained from these experiments will further our understanding of lineage choice decisions between mast cells and basophils and elucidate potential therapeutic targets for inflammatory and autoimmune disorders. PUBLIC HEALTH RELEVANCE: All cells of the hematopoietic lineage, including red blood cells, platelets and white blood cells, can arise from the same single precursor stem cell. This stem cell must go through unique development steps (lineage choices) that involve the activation or suppression of specific genes in order to develop correctly into the various cell types of our blood system. Our studies focus on the development of mast cells and basophils, highly related cells that not only are the major cause of allergic symptoms, but are also critical for some protective functions of our immune system: Here we propose to study the mechanisms by which a common precursor cell chooses to become a mast cell or basophil.