Analyzing dendritic cell development by inducible lineage tracing

通过诱导谱系追踪分析树突状细胞发育

• 批准号: 9101974
• 负责人: Boris Reizis
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101974
• 关键词: Adoptive Transfer; Adult; Antigens; Bone Marrow; Cells; Dendritic Cells; Dependence; Development; Gene Targeting; Genes; Genetic Recombination; Health; Hematopoietic stem cells; Immune; Immune response; Interferon Type I; Interferons; Kinetics; Label; Ligands; Link; Modeling; Molecular; Molecular Profiling; Mouse Strains; Mus; Organism; Population; Property; Reporter; Sentinel; Tamoxifen; Transgenic Mice; Transplantation; Update; Vaccine Design; Work; adaptive immunity; base; cell type; cytokine; in vivo; novel; pathogen; progenitor; recombinase; stem; stem cell differentiation

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are key immune sentinels that link innate recognition of pathogens to adaptive immune responses. DCs comprise two main evolutionarily conserved subsets, type I interferon- producing plasmacytoid DCs (pDCs) and antigen-presenting classical DCs (cDCs). The two DC subsets share common dependence on the cytokine Flt3 ligand, yet their cellular and molecular properties are very distinct. It is currently believed that cDCs and pDCs develop from a common DC progenitor (CDP) in the bone marrow. However, some recent evidence is not compatible with this model, warranting an unbiased re-examination of DC development using lineage tracing in vivo. We will use transgenic mouse strains expressing a tamoxifen-inducible Cre recombinase (CreER) to label stem/progenitor populations and trace their differentiation into DCs. Specifically, we will examine the kinetics and sequence of hematopoietic stem cell differentiation into DC subsets (Aim 1) and the differentiation potential of CDPs (Aim 2). These studies would generate an updated model of DC development based on in vivo lineage tracing. They would also generate novel strains for inducible Cre recombination with utility for lineage tracing and gene targeting.

描述（由申请人提供）：树突状细胞（DC）是将病原体的先天识别与适应性免疫反应联系起来的关键免疫哨兵。 DC 包括两个主要的进化保守亚群：产生 I 型干扰素的浆细胞样 DC (pDC) 和抗原呈递经典 DC (cDC)。这两个 DC 亚群对细胞因子 Flt3 配体具有共同的依赖性，但它们的细胞和分子特性却非常不同。目前认为，cDC 和 pDC 由骨髓中的共同 DC 祖细胞 (CDP) 发育而来。然而，最近的一些证据与该模型不兼容，需要使用体内谱系追踪对 DC 发育进行公正的重新检查。我们将使用表达他莫昔芬诱导型 Cre 重组酶 (CreER) 的转基因小鼠品系来标记干细胞/祖细胞群体并追踪它们向 DC 的分化。具体来说，我们将检查 造血干细胞分化为 DC 亚群的动力学和序列（目标 1）以及 CDP 的分化潜力（目标 2）。这些研究将生成基于体内谱系追踪的 DC 发育的更新模型。他们还将产生用于诱导型 Cre 重组的新菌株，并可用于谱系追踪和基因靶向。