Mapping the impact of sex hormones on macrophage fates and functions

绘制性激素对巨噬细胞命运和功能的影响

• 批准号: 10613870
• 负责人: Brittany Anne Goods
• 金额: $ 31.07万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613870
• 关键词: Address; Behavior; Biological Assay; Biology; Breast; Cell physiology; Cells; Chromatin; Complex; Coupled; Disease; Dose; Endocrine system; Female; Fertilization; Genetic Transcription; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Immune; Immune system; Infection; Knowledge; Maps; Molecular; Organism; Pathogenicity; Periodicity; Phenotype; Population; Regulatory Element; Research; Resistance; Role; System; Systems Biology; Time; Tissues; Transposase; cell type; chemokine; cytokine; interest; macrophage; monocyte; pathogen; programs; reproductive tract; single-cell RNA sequencing; transcriptome

Cellular and molecular functions in hormonally-controlled tissues, like the female reproductive tract (FRT) and breast, are coordinately controlled by both the endocrine system and the immune system. Immune cells of the FRT must maintain a microenvironment that simultaneously is permissible to fertilization but resistant to foreign pathogens and infection, resulting in a complex milieu of cell types and states. Cyclic changes in steroid sex hormone levels within the FRT and breast, coupled with heterogenous physical compartments in the FRT that each have distinct chemokine, cellular, and metabolite profiles, necessitate a systems-level approach to evaluating the fates and functions of these cells. Of particular interest in are monocytes and macrophages, both tissue resident and monocyte-derived, due to their diverse functions in homeostatic and pathogenic conditions, and their ability to rapidly adapt to shifting tissue milieus. Despite their importance to health and disease, there is a paucity of studies that have used systems approaches to understand the impact of sex hormones on macrophages. We will specifically address this outstanding knowledge gap by employing a systems biology approach to comprehensively characterize the impact that sex hormones have on macrophage fates and functions. We will first deeply profile how hormones impact the functions and transcriptomes of macrophages as a function of exposure time and dose (Aim 1). We will then use longitudinal single-cell RNAs-sequencing (scRNA-seq) and assay for transposase-accessible chromatin followed by sequencing (scATAC-seq) in order to fully map transcriptional and regulatory impacts of sex hormones on the differentiation of monocytes into macrophages (Aim 2). Taken together, by computationally inferring differentiation trajectories, identifying key regulatory elements that underpin how sex hormones modify macrophage behavior, and assessing cytokine secretion phenotypes, we will build a systems level understanding of the cellular programs that are modified by sex hormones to drive specialized macrophage fates and functions. This research has long-term implications for rationally orchestrating macrophage functions and has practical implications for understanding the diverse roles of macrophages populations in hormonally-controlled tissues.

女性生殖道（FRT）和乳腺等生殖控制组织中的细胞和分子功能由内分泌系统和免疫系统协调控制。FRT的免疫细胞必须维持一个微环境，该微环境同时允许受精但抵抗外来病原体和感染，从而导致细胞类型和状态的复杂环境。类固醇性激素水平在FRT和乳房内的周期性变化，加上FRT中的异质性物理隔室，每个隔室都有不同的趋化因子，细胞和代谢产物谱，需要系统水平的方法来评估这些细胞的命运和功能。特别令人感兴趣的是单核细胞和巨噬细胞，既有组织驻留的，也有单核细胞衍生的，这是由于它们在稳态和致病条件下的不同功能，以及它们快速适应变化的组织环境的能力。尽管它们对健康和疾病很重要，但很少有研究使用系统方法来了解性激素对巨噬细胞的影响。我们将通过采用系统生物学方法来全面表征性激素对巨噬细胞命运和功能的影响，专门解决这一突出的知识差距。我们将首先深入分析激素如何影响巨噬细胞的功能和转录组作为暴露时间和剂量的函数（目的1）。然后，我们将使用纵向单细胞RNA测序（scRNA-seq）和转座酶可接近染色质的测定，然后测序（scATAC-seq），以全面绘制性激素对单核细胞分化为巨噬细胞的转录和调节影响（目标2）。总之，通过计算推断分化轨迹，确定性激素如何改变巨噬细胞行为的关键调控因素，并评估细胞因子分泌表型，我们将建立一个系统水平的理解性激素改变的细胞程序，以驱动专门的巨噬细胞的命运和功能。这项研究对合理协调巨噬细胞功能具有长期意义，并对理解巨噬细胞群体在受神经控制的组织中的不同作用具有实际意义。