Ikaros in mast vs. basophil lineage choice

肥大与嗜碱性粒细胞谱系选择中的 Ikaros

• 批准号: 7876311
• 负责人: Melissa A Brown
• 金额: $ 22.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876311
• 关键词: Affinity; Allergic; Alternative Splicing; Autoimmune Diseases; B-Lymphocytes; Basophilia; Basophils; Blood; Blood Platelets; CCAAT-Enhancer-Binding Proteins; Cell Lineage; Cell physiology; Cells; Chromatin; Chronic; Coagulation Process; Commit; Complex; Cytokine Gene; Data; Defect; Development; Epigenetic Process; Erythrocytes; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Growth; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hypersensitivity; IL4 gene; IgE Receptors; Immune System Diseases; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Interleukin-4; Knockout Mice; Laboratories; Lead; Leukocytes; Light; Lymphoid; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Molecular Profiling; Molecular Target; Multiple Sclerosis; Mus; Natural Killer Cells; Pathogenesis; Pathway interactions; Pattern; Process; Production; Protein Isoforms; Regulation; Relative (related person); Reporting; Rheumatoid Arthritis; Role; Stem cells; Symptoms; System; T-Lymphocyte; Testing; Tissues; Wound Healing; cell type; factor C; fetal; granulocyte; improved; in vivo; leukemia; mast cell; mouse development; novel; oxygen transport; precursor cell; preference; progenitor; public health relevance; research study; response; therapeutic target; transcription factor

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.

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的晦涩细胞，其主要作用是诱导过敏。但是，在过去几年中，越来越多的证据阐明了它们在免疫系统的启动和调节中的关键作用。还很明显的是，这些细胞的功能不当对于慢性炎症性和自身免疫性疾病（如多发性硬化症和类风湿关节炎，甚至癌症）的发病机理至关重要。因此，了解这些细胞的本体发育和发展已成为必要。考虑到肥大细胞和嗜碱性物质在几个方面相似的事实，包括高亲和力IgE受体的相对独特表达并共享共同的激活，脱粒和介体释放的模式，因此它们也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由常见的造血前体 - 嗜碱性粘液乳细胞前体（BMCP）产生。然而，尚不清楚指导肥大细胞与嗜碱性粒细胞之间指导谱系选择的分子机制。据报道，与粒细胞相关的转录因子CCAAT/增强子结合蛋白1（C/EBP1）的据报道，将共同的前体转向嗜碱性粒细胞谱系。我们最近证明，转录因子Ikaros调节肥大细胞IL-4基因表达。此外，我们实验室的初步数据表明，Ikaros参与了肥大细胞的发育，并且没有Ikaros，默认细胞默认为嗜碱性嗜嗜碱性谱系。在此提案中，我们假设转录因子Ikaros将BMCP的谱系选择驱动到肥大细胞谱系。如这些目标中所述，我们将首先确定Ikaros是否使用Ikaros-null小鼠以细胞的固有方式来调节对肥大细胞的谱系选择。其次，我们将确定ikaros是否抑制了嗜碱性血统，从而促进了转录因子，例如C/EBP1。最后，我们将通过分析ikaros-null小鼠的嗜碱性粒细胞特异性反应来评估肥大与嗜碱性粒细胞发育中Ikaros损失的体内相关性。从这些实验中获得的结果将进一步理解肥大细胞和嗜碱性粒细胞之间的谱系选择决策，并阐明炎症和自身免疫性疾病的潜在治疗靶标。 公共卫生相关性：造血谱系的所有细胞，包括红细胞，血小板和白细胞，都可能来自同一单一前体干细胞。该干细胞必须经过独特的开发步骤（谱系选择），涉及特定基因的激活或抑制，以正确地发展到我们的血液系统的各种细胞类型中。我们的研究集中于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，而且对于我们的免疫系统的某些保护功能也至关重要：我们在这里建议研究一种常见的前体细胞选择成为肥大细胞或巴斯博质的机制。