Determining the genetic control of dendritic cell subsets

确定树突状细胞亚群的遗传控制

• 批准号: RGPIN-2014-06531
• 负责人: Lesage, Sylvie
• 金额: $ 2.99万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=657261
• 关键词: Determining; genetic; control; dendritic; cell

Dendritic cells, or DCs, were first described by the Nobel laureate, Dr. Ralph Steinman, over thirty years ago. DCs are white blood cells which play contrasting roles in the immune response. In the absence of infection they tone down the immune response, while in the presence of infection they are the most potent cell type for inducing an immune response.**Since their first description, multiple dendritic subsets have been identified, each bearing unique properties and contributing to different aspects of the immune response. In particular, two main resident conventional DCs are found in the spleen, which are recognized by their reciprocal expression of two proteins, namely CD8a and CD11b. Of interest, mice present with a greater proportion of CD11b+ DC than CD8a+ DC in the spleen. To understand the bias in favor of the CD11b+ DC subset, the ontogeny of DC has been investigated. It is now clear that both CD8a+ and CD11b+ DC subsets originate from cells in the bone marrow. A common cellular precursor has also been identified. Still, the reason for this imbalance in favor of the CD11b+ cDC subset remains to be elucidated.**This research program aims to address this biological question by undertaking an unbiased genetic linkage approach to unravel genes linked to the higher proportion of CD11b+ DC. By investigating the regulation of DC subset variations in inbred strain of mice, for which the genetic code has been established, we will identify a limited set of genes potentially regulating the ratio of CD8a+ to CD11b+ cDC subset. The contribution of these genes will be validated in both in vitro and in vivo model systems. In addition, by exploiting a novel reporter mouse model, we will refine the in vivo differentiation route of cDC subsets. Together, this work will improve our understanding of the genetic, molecular and cellular parameters involved in the differentiation and the homeostatic regulation of the two main cDC subsets, namely CD8a+ to CD11b+ cDCs. In addition, this research program will contribute to the training of at least four highly qualified personnel, namely two graduate students and two undergraduate students.

30多年前，诺贝尔奖得主拉尔夫·斯坦曼博士首次描述了树突状细胞。树突状细胞是白细胞，在免疫反应中起着不同的作用。在没有感染的情况下，它们会减弱免疫反应，而在有感染的情况下，它们是诱导免疫反应最有效的细胞类型。**自首次描述以来，已确定了多个树突亚群，每个亚群都具有独特的特性，并对免疫反应的不同方面做出贡献。特别是，在脾脏中发现了两种主要的常驻常规dc，它们通过CD8a和CD11b两种蛋白质的相互表达来识别。有趣的是，小鼠脾脏中CD11b+ DC的比例高于CD8a+ DC。为了理解对CD11b+ DC亚群的偏爱，研究人员对DC的个体发生进行了研究。现在很清楚CD8a+和CD11b+ DC亚群都起源于骨髓细胞。一个共同的细胞前体也已被确定。尽管如此，这种有利于CD11b+ cDC亚群的不平衡的原因仍有待阐明。**本研究计划旨在通过采用无偏倚的遗传连锁方法来解开与CD11b+ DC比例较高相关的基因，从而解决这一生物学问题。通过研究已建立遗传密码的小鼠近交系DC亚群变异的调控，我们将确定一组有限的基因可能调控CD8a+与CD11b+ cDC亚群的比例。这些基因的贡献将在体外和体内模型系统中得到验证。此外，通过开发一种新的报告小鼠模型，我们将完善cDC亚群的体内分化途径。总之，这项工作将提高我们对两种主要cDC亚群（CD8a+到CD11b+）的分化和稳态调节所涉及的遗传、分子和细胞参数的理解。此外，本研究计划将有助于培养至少四名高素质人才，即两名研究生和两名本科生。