Genetic determinants of myeloid cell homeostasis and tissue distribution

骨髓细胞稳态和组织分布的遗传决定因素

• 批准号: 10005591
• 负责人: Gaelle Breton
• 金额: $ 21.74万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005591
• 关键词: Address; Affect; Age; Animal Model; Autoimmune Diseases; Bone Marrow; Candidate Disease Gene; Cell Count; Cells; Chromosome Mapping; Data; Data Set; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Equilibrium; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genotype; Health; Homeostasis; Human; Immune; Immune system; Immunologic Deficiency Syndromes; Individual; Knowledge; Link; Lymphoid; Malignant Neoplasms; Maps; Mus; Myeloid Cells; Myelopoiesis; Pathology; Peripheral; Play; Population; Predisposition; Public Health; Quantitative Trait Loci; Reproducibility; Resolution; Resources; Role; Source; System; Testing; Tissues; Twin Studies; Validation; Variant; cell type; experimental study; granulocyte; high dimensionality; immunological diversity; in vivo; insight; latent infection; monocyte; progenitor; sex

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. !

项目摘要 髓系细胞的寿命相对较短，必须不断更新才能维持正常 体内平衡最近的研究结果表明，免疫细胞稳态的变化存在于 个体虽然年龄、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 决定论这个提议的目的是为了理解宿主多态性在 使用协作杂交（CC）和多样性远交（DO）动物的稳态稳态 反映远交种群（如人类）遗传多样性的模型。这些菌株 是高分辨率遗传作图的理想资源，因此将提供强大的 一个实验系统，以测试这一假设的变化，在骨髓细胞稳态是遗传 管理，并绘制多样性的来源。我们首先建议进行一项全面的 筛选CC和DO菌株的全身和组织水平的髓样细胞，以估计 自然遗传变异导致的多样性（目标1）。利用高分辨率QTL作图 在DO中，我们将鉴定出髓样细胞稳态和组织中变异的基础基因， 我们将使用CC菌株进行这些基因的体内实验验证， 机制研究（目标2）。本项目提出的所有探索性实验 代表了阐明基因型和免疫细胞数量之间联系的主要努力 并将提供一个丰富的资源，询问自我平衡机制， 组织中免疫细胞的平衡。 !