Early Innate Lymphoid Cell Development

早期先天淋巴细胞发育

• 批准号: 9034021
• 负责人: Qi yang
• 金额: $ 16.2万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034021
• 关键词: Adoptive Transfer; Adult; Affect; Alternaria; Antigen Receptors; Asthma; Biology; Bone Marrow; Bone Marrow Cells; Cell Lineage; Cells; Cellular biology; Characteristics; Coculture Techniques; Data; Development; Disease; Ectopic Expression; Event; Foundations; Gene Expression Profile; Generations; Genes; Goals; Health; Hematopoiesis; Homeostasis; Host Defense; Human; ID2 gene; Immune; In Vitro; Infection; Inflammation; Lead; Light; Lung; Lymphoid Cell; Maintenance; Molecular; Mouse Strains; Mus; Organism; Pathogenesis; Pathway interactions; Peripheral; Play; RNA Sequence Analysis; Regulation; Regulatory Pathway; Reporter; Research; Role; Signal Transduction; Signaling Molecule; Specific qualifier value; Structural Genes; T-Cell Development; T-Lymphocyte; TCF Transcription Factor; Testing; Tissues; To specify; Work; airway inflammation; allergic airway inflammation; cell fate specification; combat; in vivo; inhibitor/antagonist; insight; mucosal site; new therapeutic target; novel; progenitor; programs; research study; self-renewal; transcriptome

 DESCRIPTION (provided by applicant): The goal of my independent research program is to understand the mechanisms that control innate lymphoid cell (ILC) replenishment and differentiation in homeostasis and inflammation and how such regulation affects human health and disease. Experiments in this K22 proposal will generate essential preliminary data that lay the foundation of my independent research program. This proposal aims at discovering novel early ILC progenitors, exploring their importance in homeostasis and airway inflammation, and identifying the major molecules that drive early ILC development. Innate lymphoid cells are important players in host defense, tissue remodeling, and asthma pathogenesis. However, little is known about the cellular and molecular mechanisms that drive early ILC development. The transcriptional regulators TCF-1 and Id2 are required for the efficient generation of all known adult ILC subsets. I hypothesize that TCF-1 and Id2 are expressed at the earliest ILC progenitors and together drive early ILC development. Using new TCF-1gfp reporter mouse strain, I discovered a novel subset of early innate lymphoid cell progenitor (EILP) in the bone marrow and in the lung. EILP expressed TCF-1 and Id2, and efficiently differentiated into all four ILC lineages at the clonal level, indicating that they are the earliest identifiable ILC progenitor. I will use adoptive transfer and serial-transfer approaches to test whether EILP are the self-renewing progenitors that replenish non-circulating pulmonary ILC in homeostasis and during Alternaria-induced allergic airway inflammation. Using retroviral TCF-1 and Id2 co- transduction, I found that co-expression of both TCF-1 and Id2, but not either alone, elicited the emergence of ILC-committed progenitors in vitro. I will compare the transcriptomes of these TCF-1 and Id2 co-elicited progenitors with those of the in vivo early ILC progenitors to interrogate the gene program controlled by TCF-1 and Id2. I will further compare the transcriptomes of lung-resident EILP with those of bone marrow EILP and the in vitro TCF-1/Id2 co-elicited progenitors to explore whether lung microenvironments may elicit additional signals to support local ILC replenishment and differentiation. Together, these experiments will shed light on the hematopoiesis pathway that lead to ILC replenishment in the adult organism and will reveal the key gene regulatory pathways that drive early ILC development. The data generated will provide new insights into ILC biology and will suggest new therapeutic targets for ILC-related diseases such as asthma.

 描述（由申请人提供）：我的独立研究项目的目标是了解控制先天淋巴细胞（ILC）补充和分化的机制，以及这种调节如何影响人类健康和疾病。K22提案中的实验将产生重要的初步数据，为我的独立研究计划奠定基础。该提案旨在发现新的早期ILC祖细胞，探索它们在体内平衡和气道炎症中的重要性，并确定驱动早期ILC发展的主要分子。先天性淋巴样细胞在宿主防御、组织重塑和哮喘发病机制中起重要作用。然而，很少有人知道的细胞和分子机制，驱动早期ILC的发展。转录调节因子TCF-1和Id 2是有效产生所有已知的成人ILC亚群所必需的。我推测TCF-1和Id 2在最早的ILC祖细胞中表达，并共同驱动早期ILC的发展。使用新的TCF-1gfp报告小鼠品系，我发现了一个新的早期先天淋巴样细胞祖细胞（EILP）在骨髓和肺的子集。EILP表达TCF-1和Id 2，并在克隆水平上有效地分化为所有四种ILC谱系，表明它们是最早可鉴定的ILC祖细胞。我将使用过继转移和连续转移的方法来测试EILP是否是自我更新的祖细胞，在体内平衡和链格孢菌诱导的过敏性气道炎症过程中补充非循环肺ILC。使用逆转录病毒TCF-1和Id 2共转导，我发现TCF-1和Id 2两者的共表达，但不是单独的，在体外引起ILC定向祖细胞的出现。我将比较这些TCF-1和Id 2共同诱导的祖细胞的转录组与体内早期ILC祖细胞的转录组，以询问由TCF-1和Id 2控制的基因程序。我将进一步比较肺驻留EILP的转录组与骨髓EILP和体外TCF-1/Id 2共同诱导的祖细胞的转录组，以探索肺微环境是否可以引发额外的信号来支持局部ILC的补充和分化。总之，这些实验将揭示造血途径，导致ILC补充成人生物体，并将揭示关键的基因调控途径，驱动早期ILC的发展。所产生的数据将为ILC生物学提供新的见解，并为哮喘等ILC相关疾病提供新的治疗靶点。