Fibroblast dysregulation promotes dermal eosinophilic/Th2 inflammation

成纤维细胞失调促进真皮嗜酸性/Th2炎症

基本信息

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
项目类别：
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

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

展开

项目摘要

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疾病之一成人的患病率接近5％，通常以小儿发作，瘙痒和持久性为特征。研究表明，AD与受损的上皮屏障相关环境抗原和II型免疫反应。尽管广告研究取得了进步，但原因是导致II型免疫反应的机制尚不清楚。我们最近的出版物和 PREL数据表明，真皮和亚库包含的成纤维细胞似乎涉及建立类型 II皮肤炎症反应。了解皮肤成纤维细胞的失调如何有助于他们可能会促进炎症性广告样病变形成的下游事件是其中的重点提议。我们的准备数据表明，PRX1+成纤维细胞中NF-KB信号的失调导致CEBPB上调在成纤维细胞中，CCL11和组织嗜酸性粒细胞的上调，然后是II型皮肤病变的上调广告。我们的鼠标模型与涉及真皮和类似人类广告的病变具有许多相似之处在组织学，细胞和分子水平的表皮。 PREL数据比较了单细胞RNASEQ分析我们对人类广告病变发表的SCRNASEQ数据库的研究。来自我们的模型和人AD显示涉及CCL11和CEBPB的成纤维细胞失调。而且，使用rnascope我们也有表明经过验证的人类广告样品包含增加的皮肤成纤维细胞，共表达CEBPB 与匹配的对照人皮肤相比，CCL11也与我们的鼠模型一致。因此，我们建议新颖的临床前和翻译研究（目标1）来定义成纤维细胞的分子机制 CEBPB介导的失调诱导这些细胞的炎症表型。 AIM 2将确定嗜酸性粒细胞浸润作为触发AD样皮肤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以及使用抑制剂作为AD的潜在治疗方法的AD标本和翻译研究。我们期望拟议的研究以及文献中的最新报告，以促进理解的范式转变有关成纤维细胞失调的AD发病机理，并有助于新治疗的发展可能阻止AD发展的干预措施。