Ikaros in mast vs. basophil lineage choice

描述（由申请人提供）：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模糊的细胞，其主要作用是诱导过敏。然而，在过去的几年里，越来越多的证据表明它们在免疫系统的启动和调节中起着关键作用。同样明显的是，这些细胞的功能不正常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）发病机制的核心。因此，了解这些细胞的个体发生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相似的事实，包括高亲和力IgE受体的相对独特的表达，并共享共同的激活，脱粒和介质释放模式，它们也具有平行的发育途径并不奇怪。据报道，肥大细胞和嗜碱性粒细胞产生于一个共同的造血前体-嗜碱性肥大细胞前体（BMCP）。然而，指导肥大细胞与嗜碱性粒细胞之间谱系选择的分子机制尚不清楚。据报道，粒细胞相关转录因子CCAAT/增强子结合蛋白1（C/EBP 1）引导共同前体向嗜碱性细胞谱系发展。我们最近证明，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谱系。在这个提议中，我们假设转录因子Ikaros驱动BMCP向肥大细胞谱系的谱系选择。如在这些目标中所述，我们将首先使用Ikaros缺失小鼠确定Ikaros是否以细胞内在方式以嗜碱性粒细胞为代价调节对肥大细胞的谱系选择。其次，我们将确定Ikaros是否抑制嗜碱性细胞谱系促进转录因子，如C/EBP 1。最后，我们将通过分析Ikaros缺失小鼠中嗜碱性粒细胞特异性反应来评估肥大细胞与嗜碱性粒细胞发育中Ikaros缺失的体内相关性。从这些实验中获得的结果将进一步了解肥大细胞和嗜碱性粒细胞之间的谱系选择决定，并阐明炎症和自身免疫性疾病的潜在治疗靶点。 公共卫生相关性：造血谱系的所有细胞，包括红细胞、血小板和白色血细胞，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展，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至关重要：在这里，我们建议研究一个共同的前体细胞选择成为肥大细胞或嗜碱性粒细胞的机制。

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.