Quantifying gene expression and network regulation in single cells to reveal the consequences of stress on the immune response

量化单细胞中的基因表达和网络调控，揭示压力对免疫反应的影响

• 批准号: 10294937
• 负责人: Paul L Maurizio
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294937
• 关键词: Address; Affect; Age; Animals; Area; Atlases; Autoimmunity; Automobile Driving; Bacterial Infections; Basic Science; Blood Cells; Cell Communication; Cells; Chronic; Communicable Diseases; Data; Disease; Disease susceptibility; Environment; Environmental Risk Factor; Experimental Models; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunity; Immunization; Immunology; Individual; Infection; Infection prevention; Inflammatory; Influentials; Knowledge; Link; Lipopolysaccharides; Macaca mulatta; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Methods; Modeling; Modernization; Molecular; Molecular Profiling; Outcome; Paracrine Communication; Pathway Analysis; Pathway interactions; Peripheral Blood Mononuclear Cell; Physiology; Play; Population; Postdoctoral Fellow; Predisposition; Primates; Property; Regulation; Regulator Genes; Research; Resources; Risk; Role; Signal Pathway; Signal Transduction; Social Dominance; Social Environment; Social Gradients; Social Hierarchy; Social status; Statistical Models; Stress; Technology; Testing; Therapeutic Effect; Training; Variant; Whole Blood; Work; age effect; cancer risk; cell type; clinically relevant; design; disorder risk; experience; gene expression variation; genome-wide; human model; immune function; immunoregulation; improved; inter-individual variation; mortality; next generation; non-genetic; pathogen; peripheral blood; programs; response; sex; single-cell RNA sequencing; social; social group; social inequality; social stress; targeted treatment; tumor growth

PROJECT SUMMARY Human health is profoundly affected by genetics and the environment. The social environment mediates changes in physiology, gene regulation, and immune signaling, resulting in significant differences in disease susceptibility and mortality. Chronic social stress and social inequity are major drivers of disease, in part due to effects on the immune response to infectious pathogens. However, the molecular mechanisms underlying these effects are poorly understood. In order to address this gap, robust experimental models for uncovering social environmental effects on the immune system are needed. Rhesus macaques are primates closely related to humans. In social groups, they maintain stable hierarchies of social dominance, and these hierarchies can be experimentally manipulated through social group rearrangement. Thus, they provide a unique resource to study causal social rank effects on disease. Although significant and substantial gene expression changes in peripheral blood have been found to be associated with social rank, the cell types underlying these signatures are not well-characterized. Single-cell RNA-sequencing enables the discovery of effects of the social environment on individual cells of many kinds, which can help with the targeting of clinically-relevant cell types that are responsible for immune dysregulation. Therefore, this work proposes to study rank effects on gene regulation in individual peripheral blood cells, at baseline and after immune stimulation, to uncover cell-type-specific social stress effects on immunity. The basic research question driving this proposal is: How does the social environment affect gene expression across diverse peripheral blood immune cells? To answer this question, the approach of this proposal is to use a well-established model of social adversity in captive female rhesus macaques, and to apply next- generation single-cell RNA-seq technology to deeply characterize cells isolated from 50 individuals across a social gradient. From this data, effects of social rank will be examined for: (1) immune composition and LPS- induced polarization, (2) gene expression robustness across cell types, and (3) gene regulatory networks and co-expression modules. Through this work, clinically-relevant genes and pathways will be identified that are rewired by social environment effects, in order to design targeted therapeutics to improve immune responses relevant to cancer and infectious disease.

项目摘要 人类健康受到遗传学和环境的深远影响。社会环境调解 生理学，基因调节和免疫信号传导的变化，导致疾病的显着差异 敏感性和死亡率。慢性社会压力和社会不平等是疾病的主要驱动力，部分原因是 对传染病的免疫反应的影响。但是，这些分子机制是这些机制 效果知之甚少。为了解决这一差距，可识别社会的强大实验模型 需要对免疫系统的环境影响。 恒河猕猴是与人类密切相关的灵长类动物。在社会团体中，他们保持稳定 社会主导地位的层次结构以及这些等级制度可以通过社会群体进行实验操纵 重排。因此，它们提供了一种独特的资源来研究因果关系对疾病的影响。虽然 已经发现周围血液中的显着和实质基因表达变化与 社会等级，这些签名的细胞类型没有很好地表征。单细胞RNA序列 实现社会环境对多种单元的影响的影响，这可以帮助您 负责免疫失调的临床临床相关细胞类型的靶向。因此，这项工作 提议研究对单个外周血细胞，基线和之后对基因调控的秩对基因调节的影响 免疫刺激，以发现细胞类型特异性的社会压力对免疫的影响。 推动此建议的基础研究问题是：社会环境如何影响基因 跨各种外周血免疫细胞的表达？为了回答这个问题，该提议的方法 是在圈养的女恒河猕猴中使用公认的社会逆境模式，并应用接下来的 一代单细胞RNA-seq技术，深刻地表征了从50个个体中分离出的细胞 社会梯度。从这些数据中，将检查社会等级的影响：（1）免疫组成和LPS- 诱导极化，（2）细胞类型之间的基因表达鲁棒性，以及（3）基因调节网络和 共表达模块。通过这项工作，将确定与临床相关的基因和途径 通过社会环境效应重新连接，以设计有针对性的治疗剂以改善免疫反应 与癌症和传染病有关。