Acne: a disease of lipid metabolism, microbiome and the immune response

痤疮：一种脂质代谢、微生物组和免疫反应疾病

• 批准号: 10404440
• 负责人: ROBERT L MODLIN
• 金额: $ 39.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404440
• 关键词: Acne; Address; Animal Model; Architecture; Bacteria; Binding; Bioinformatics; Biological; Biological Factors; Biopsy Specimen; Cell Communication; Cells; Characteristics; Chronic; Complex; Cutaneous; Data; Development; Disease; Drug resistance; Elements; Fibroblasts; Functional disorder; Genes; Genomics; Goals; Host Defense; Human; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Lesion; Link; Lipids; Maps; Mass Spectrum Analysis; Mediating; Medical; Mesenchymal Stem Cells; Metagenomics; Microbiology; Modeling; Molecular; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Population; Process; Production; Reactive Oxygen Species; Research Personnel; Research Project Grants; Research Project Summaries; Role; Sampling; Sebum; Shapes; Signal Transduction; Site; Skin; Squalene; TLR2 gene; TREM2 gene; Techniques; Testing; Time; Yang; antimicrobial; base; cathelicidin; cell type; cytokine; disability; immune activation; insight; keratinocyte; lipid metabolism; lipidome; lipidomics; macrophage; microbial; microbiome; molecular marker; network models; novel therapeutic intervention; programs; psychologic; response; side effect; single-cell RNA sequencing; skin disorder; skin microbiome; transcriptomics; treatment strategy

ABSTRACT / PROJECT SUMMARY Research Project The overall goal of UCLA/UCSD Research Project is to investigate the interaction between the microbiome, lipid metabolism and the host immune response in acne. The microbiome of the pilosebaceous unit (PSebU), the initial site where acne lesions develop, is tractable, with Cutibacterium acnes the dominant bacterium. C. acnes is considered to be one of the key contributing factors in the pathogenesis of acne. The UCLA/UCSD Research Project is based on our recent findings using transcriptomics, metagenomics and lipidomics, establishing the goal to link together these diverse biologic responses into a model that may explain the pathogenesis of acne. By applying single cell RNA-sequencing (scRNA-seq) and spatial-seq, the Modlin and Gallo labs have together identified specific macrophage and mesenchymal stem cell fibroblasts subpopulations that occur in acne lesions as compared to uninvolved skin from the same patients. Surprisingly, we detected a large population of TREM2 macrophages, previously identified in diseases characterized by altered lipid metabolism, in acne lesions expressing both lipid metabolism and pro-inflammatory gene programs. We found that squalene, a component of sebum, induced TREM2 macrophages in vitro that were not antimicrobial, in part because squalene inhibited production of and scavenged oxygen radicals that kill C. acnes. Furthermore, acne lesions also contain a unique inflammatory fibroblast subpopulation that undergoes an adipogenic trajectory and produces pro-inflammatory cathelicidin in a TLR2 dependent manner, implicating for the first time the perifollicular fibroblast as a critical contributor to acne inflammation. The UCLA/UCSD Research Project (Modlin, Gallo), “Acne: a disease of lipid metabolism, microbiome and the immune response”, will initially focus studies on the role of TREM2 macrophages and adipogenic fibroblasts in the pathogenesis of acne. The project investigators will obtain acne biopsy specimens (Hata, Kim), then address the link between the immune response in acne lesions to the microbiome and lipid metabolism. The Research Project will be supported by a UCLA Bioinformatics Core (Pellegrini, Yang) to analyze scRNA-seq and spatial-seq of acne lesions, a UCSD Microbiology and Metagenomics Core (Gallo, O’Neill) to isolate and characterize C. acnes strains, and lipidomics analysis (Bensinger, UCLA) of biopsy specimens and key cell types derived in vitro. Ultimately, Bioinformatics core will use mergeomics to combine data from transcriptomics, metagenomics and lipidomics to create a network model of the pathogenesis of acne. The proposed studies will provide new insights into how lipid metabolism and the skin microbiome shapes cutaneous immune responses contributing to inflammation, with the potential for intervention in skin disease.

摘要/项目摘要 研究项目 UCLA/UCSD研究项目的总体目标是调查微生物群之间的相互作用， 痤疮的脂代谢和宿主免疫反应。毛脂腺单位的微生物组(PSebU)， 痤疮皮损发生的最初部位很容易处理，痤疮皮肤杆菌是优势细菌。C。 痤疮被认为是痤疮发病的关键因素之一。加州大学洛杉矶分校/加州大学洛杉矶分校 研究项目基于我们使用转录组学、元基因组学和脂类组学的最新发现， 建立目标，将这些不同的生物反应联系在一起，形成一个模型，可以解释 痤疮的发病机制。通过应用单细胞RNA测序(scRNA-seq)和空间序列，modlin和 盖洛实验室共同鉴定了特定的巨噬细胞和间充质干细胞成纤维细胞亚群。 与同一患者的正常皮肤相比，痤疮皮损中会出现这种情况。令人惊讶的是，我们检测到一个 大量TREM2巨噬细胞，以前在以脂质改变为特征的疾病中发现 新陈代谢，在痤疮皮损中同时表达脂肪代谢和促炎基因程序。我们发现 角鲨烯，皮脂的一种成分，在体外诱导了TREM2巨噬细胞，这些巨噬细胞没有抗菌作用，在 部分原因是角鲨烯抑制了杀死痤疮假丝酵母菌的氧自由基的产生和清除。此外， 痤疮皮损还包含一种独特的炎性成纤维细胞亚群，该亚群经历了成脂过程。 以TLR2依赖的方式跟踪并产生促炎症的长春花碱，这是第一次 将卵泡周围成纤维细胞作为痤疮炎症的关键因素。加州大学洛杉矶分校/加州大学圣地亚哥分校的研究 项目(莫德林，加洛)，“痤疮：一种脂类代谢、微生物组和免疫反应的疾病”，威尔 初步研究TREM2巨噬细胞和成脂成纤维细胞在糖尿病发病机制中的作用 粉刺。项目调查人员将获得痤疮活检样本(HATA，KIM)，然后解决 痤疮皮损对微生物群和脂类代谢的免疫反应。研究项目将是 由加州大学洛杉矶分校生物信息学核心(Pellegrini，Yang)支持分析痤疮的scRNA-seq和空间-seq 皮损，UCSD微生物学和元基因组学核心(Galo，O‘Neill)分离和鉴定痤疮念珠菌 对活体标本和体外衍生的关键细胞类型进行脂质组学分析(Bensinger，UCLA)。 最终，生物信息学核心将使用合并组学来结合转录组学、元基因组学和 脂质组学创建了痤疮发病机制的网络模型。拟议的研究将提供新的 对脂肪代谢和皮肤微生物群如何塑造皮肤免疫反应的洞察 对于炎症，有可能干预皮肤病。