Genetic determinants of myeloid cell homeostasis and tissue distribution

项目摘要 髓系细胞的寿命相对较短，必须持续更换才能维持正常 动态平衡。最近的发现表明，免疫细胞的动态平衡存在差异 个人。尽管年龄、性别和潜伏感染等非遗传因素会影响 免疫细胞频率的变化，来自双胞胎研究的数据表明高水平的遗传 决定论。这项建议的目的是要认识到宿主多态在 利用合作杂交(CC)和多样性近交系(DO)动物实现稳态动态平衡 反映人类等异种繁殖群体的遗传多样性的模型。这些菌株 是高分辨率基因图谱的理想资源，因此将提供强大的 验证髓系细胞稳态变异是遗传因素假说的实验系统 监管，并绘制多样性的来源。我们首先提议进行一项全面的 筛选CC和DO株的全身性和组织性髓系细胞水平 自然遗传变异产生的多样性(目标1)。利用高分辨率QTL作图 因此，我们将确定导致髓系细胞动态平衡和组织变异的基因 分布；我们将使用CC菌株进行体内实验验证这些基因和 机械论研究(目标2)。本项目中提出的所有探索性实验 代表了阐明基因和免疫细胞数量之间的联系的主要努力。 并将提供丰富的资源来审问管理 组织中免疫细胞的平衡。 好了！

Project Summary Myeloid cells are relatively short-lived, and must be continuously replaced to maintain normal homeostasis. Recent findings showed that variation in immune cell homeostasis exists between individuals. Although non-heritable factors such as age, sex and latent infections can affect variation in immune cell frequencies, data from twin studies suggest a high level of genetic determinism. The object of this proposal is to appreciate the role that host polymorphisms play in steady-state homeostasis using the Collaborative Cross (CC) and Diversity Outbred (DO) animal models that reflect the genetic diversity of an outbred population such as humans. These strains are an ideal resource for high-resolution genetic mapping and will therefore provide a powerful experimental system to test the hypothesis that variation in myeloid cell homeostasis is genetically regulated, and to map the source of the diversity. We first propose to conduct a comprehensive screen of CC and DO strains for systemic and tissue levels of myeloid cells to estimate the diversity resulting from natural genetic variation (Aim 1). Using high-resolution QTL mapping in the DO, we will identify genes that underlie variation in myeloid cell homeostasis and tissue distribution; we will use CC strains for in vivo experimental validation of these genes and mechanistic studies (Aim 2). Altogether exploratory experiments proposed in this project represents a major effort to elucidate the association between genotype and immune cell numbers and will provide a rich resource for interrogating the homeostatic mechanisms governing the balance of immune cells in tissues. !