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: 10408168
• 负责人: Paul L Maurizio
• 金额: $ 7.36万
• 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 2023-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408168
• 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; 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; gene network; gene regulatory network; 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 adversity; 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.

项目概要 人类健康深受遗传和环境的影响。社会环境起到调节作用 生理、基因调控和免疫信号的变化，导致疾病的显着差异 易感性和死亡率。慢性社会压力和社会不平等是疾病的主要驱动因素，部分原因是 对传染性病原体的免疫反应的影响。然而，这些现象背后的分子机制 人们对影响知之甚少。为了弥补这一差距，需要建立强大的实验模型来揭示社会 需要了解环境对免疫系统的影响。 恒河猴是与人类关系密切的灵长类动物。在社会群体中，他们保持稳定 社会统治的等级制度，这些等级制度可以通过社会群体进行实验性操纵 重新排列。因此，它们为研究社会等级对疾病的因果影响提供了独特的资源。虽然 已发现外周血中显着且实质性的基因表达变化与 尽管社会等级不同，但这些特征背后的细胞类型尚未得到很好的表征。单细胞 RNA 测序 能够发现社会环境对多种个体细胞的影响，这有助于 针对导致免疫失调的临床相关细胞类型。因此，这项工作 提议研究基线时和之后对个体外周血细胞基因调控的排名影响 免疫刺激，揭示细胞类型特异性的社会压力对免疫的影响。 推动该提案的基本研究问题是：社会环境如何影响基因 在不同的外周血免疫细胞中表达？为了回答这个问题，本提案的方法 是在圈养雌性恒河猴中使用一种行之有效的社会逆境模型，并应用下一步- 新一代单细胞 RNA-seq 技术可深入表征从 50 个个体中分离出的细胞 社会梯度。根据这些数据，将检查社会等级的影响：（1）免疫成分和 LPS- 诱导极化，(2) 跨细胞类型的基因表达稳健性，以及 (3) 基因调控网络和 共表达模块。通过这项工作，将确定临床相关的基因和途径 通过社会环境影响重新布线，以设计有针对性的疗法来改善免疫反应 与癌症和传染病有关。

项目成果

A sexually selected male weapon characterized by strong additive genetic variance and no evidence for sexually antagonistic polyphenic maintenance.

一种性选择的男性武器，其特征是强烈的加性遗传变异，并且没有证据表明性对抗性多相维持。

• DOI: 10.1093/evolut/qpad039
• 发表时间: 2023
• 期刊: Evolution; international journal of organic evolution
• 作者: Parrett,JonathanM;Łukasiewicz,Aleksandra;Chmielewski,Sebastian;Szubert-Kruszyńska,Agnieszka;Maurizio,PaulL;Grieshop,Karl;Radwan,Jacek
• 通讯作者: Radwan,Jacek