Fibroblast dysregulation promotes dermal eosinophilic/Th2 inflammation

成纤维细胞失调促进真皮嗜酸性/Th2炎症

• 批准号: 10725870
• 负责人: DANA T GRAVES
• 金额: $ 43.05万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725870
• 关键词: ATAC-seq; Ablation; Adult; Affect; Agreement; Antibodies; Antigens; Atopic Dermatitis; Automobile Driving; Biological; Biological Markers; CCL11 gene; Cells; Childhood; Cutaneous; Data; Databases; Dermal; Dermis; Development; Disease; Disease Progression; Eosinophilia; Epidermis; Epithelium; Event; Fibroblasts; Genetic; Goals; Histologic; Homeostasis; Human; Immune; Immune response; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Lesion; Literature; Mediating; Modeling; Molecular; Molecular Target; Mus; NF-kappa B; Pathogenesis; Pathogenicity; Perinatal; Persons; Phenotype; Phosphotransferases; Prevalence; Primary Lesion; Production; Pruritus; Public Health; Publications; Publishing; RNA Interference; Reaction; Reporting; Research; Role; Sampling; Signal Transduction; Skin; Specimen; Subcutaneous Tissue; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Up-Regulation; chemokine; cost; eosinophil; experimental study; in vivo; inhibitor; insight; mouse model; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; prevent; response; single-cell RNA sequencing; skin disorder; skin lesion; skin organogenesis; small molecule therapeutics; subcutaneous; transcription factor; transcriptome sequencing; transcriptomics; translational study

Abstract: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with an estimated prevalence approaching 5% in adults and is typically characterized by pediatric onset, pruritis and persistance. Research has indicated that AD is associated with an impaired epithelial barrier that promotes sensitization to environmental antigens and a type II immune response. Despite advances in AD research, the causative mechanism(s) leading to the persistent type II immune response remain unclear. Our recent publication and Prel Data indicate that the dermis and subcutis contain fibroblasts that appear to be involved in establishing type II inflammatory reactions in skin. Understanding how dysregulation of skin fibroblasts contributes to downstream events that they may intitiate formation of inflammatory AD-like lesions is the focus of this proposal. Our Prel Data show that dysregulation of NF-kB signaling in Prx1+ fibroblasts leads to upregulation of CEBPb in fibroblasts, upregulation of CCL11 and tissue eosinophilia followed by type II skin lesions resembling human AD. Our mouse model shares many similarities with human AD-like lesions involving both the dermis and epidermis at the histologic, cellular and molecular levels. Prel Data compares single cell RNAseq analysis from our study with published scRNAseq databases from human AD lesions. scRNAseq analysis from our model and human AD show fibroblast dysregulation involving CCL11 and CEBPb. Moreover, using RNAScope we have also shown that validated human AD samples contain increased numbers of dermal fibroblasts co-expressing CEBPb and CCL11 compared to matched control human skin, also consistent with our murine model. Thus, we propose novel preclinical and translational studies (Aim 1) to define molecular mechanisms by which fibroblast dysregulation mediated by CEBPb induces an inflammatory phenotype in these cells. Aim 2 will determine the role of eosinophil infiltration as a key intermediate for triggering type II immune response in AD-like skin. Aim 3 will use spatial transcriptomics (GeoMX) and RNA seq to explore equivalent mechanisms in human fibroblasts and AD specimens and translational studies using inhibitors as potential treatments for AD. We expect the proposed studies along with recent reports in the literature to contribute to a paradigm shift in understanding AD pathogenesis regarding fibroblast dysregulation and contribute to development of new therapeutic interventions that may prevent the development of AD.

【摘要】：特应性皮炎(AD)是最常见的炎症性皮肤病之一。 成人中的患病率接近 5%，通常以儿童发病、瘙痒和持续存在为特征。 研究表明，AD 与上皮屏障受损有关，上皮屏障受损会促进对 环境抗原和 II 型免疫反应。尽管 AD 研究取得了进展，但其病因 导致持续 II 型免疫反应的机制仍不清楚。我们最近的出版物和 前期数据表明真皮和皮下组织含有似乎参与建立类型的成纤维细胞 II 皮肤炎症反应。了解皮肤成纤维细胞的失调如何导致 它们可能引发炎症性 AD 样病变形成的下游事件是本研究的重点 提议。 我们的 Prel 数据显示 Prx1+ 成纤维细胞中 NF-kB 信号传导失调导致 CEBPb 上调 在成纤维细胞中，CCL11 上调和组织嗜酸性粒细胞增多，随后出现类似于人类的 II 型皮肤病变 广告。我们的小鼠模型与人类 AD 样病变有许多相似之处，涉及真皮和 表皮的组织学、细胞和分子水平。 Prel Data 比较了单细胞 RNAseq 分析 我们的研究使用了来自人类 AD 病变的已发表的 scRNAseq 数据库。根据我们的模型进行 scRNAseq 分析 人类 AD 显示涉及 CCL11 和 CEBPb 的成纤维细胞失调。此外，使用 RNAScope 我们还 表明经过验证的人类 AD 样本中共表达 CEBPb 的真皮成纤维细胞数量有所增加 和 CCL11 与匹配的对照人类皮肤相比，也与我们的小鼠模型一致。因此，我们建议 新颖的临床前和转化研究（目标 1），以确定成纤维细胞的分子机制 CEBPb 介导的失调会在这些细胞中诱导炎症表型。目标 2 将确定 嗜酸性粒细胞浸润作为 AD 样皮肤中触发 II 型免疫反应的关键中间体的作用。目的 3 将使用空间转录组学 (GeoMX) 和 RNA seq 探索人类成纤维细胞中的等效机制 AD 标本和使用抑制剂作为 AD 潜在治疗方法的转化研究。我们期望 拟议的研究以及最近文献中的报告有助于理解范式的转变 AD 发病机制与成纤维细胞失调有关，有助于开发新的治疗方法 可能预防 AD 发展的干预措施。