Exosome-mediated Cooperative Mechanisms of Macrophage/Fibroblast Activation in Systemic Sclerosis

系统性硬化症中外泌体介导的巨噬细胞/成纤维细胞激活的协同机制

基本信息

批准号：
10441758
负责人：
Patricia A. Pioli
金额：
$ 26.04万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-25 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441758
关键词：
3-Dimensional Affect Age Autoimmune Diseases Biology Chronic Coculture Techniques Collagen Computer Analysis Cutaneous sclerosis Data Set Deposition Dermal Development Disease Disease Progression Etiology Extracellular Matrix Extracellular Matrix Proteins FDA approved Fibroblasts Fibrosis Foundations Gender Gene Expression Genomics Goals Homing Human Immune Immunologist Immunophenotyping Inflammation Inflammation Mediators Inflammatory Leukocytes Macrophage Activation Maintenance Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Molecular Biology Myeloid Cell Activation Myeloid Cells Pathogenesis Pathway interactions Patients Play Population Production Proteins Publishing Role Sampling Signal Pathway Signal Transduction Skin Standardization Systemic Scleroderma Testing Therapeutic Intervention Tissue Model Tissues Treatment Efficacy Vascular Diseases Women&apos s Health Work body system cell type chronic autoimmune disease comorbidity cytokine disease diagnosis disease phenotype effective therapy exosome experience human tissue immune activation macrophage molecular subtypes monocyte mortality new therapeutic target novel paracrine prevent profibrotic cytokine response single-cell RNA sequencing targeted treatment therapeutic evaluation tissue injury treatment strategy uptake wound healing

项目摘要

ABSTRACT Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology that is characterized by vasculopathy, fibrosis, and inflammation. There is no cure for SSc and there are very few FDA-approved disease- modifying treatments. While the contribution of fibroblasts to disease development is widely appreciated, recent studies suggest macrophages (MØs) also play a role in the pathogenesis of SSc. In recently published work, we developed an immunophenotypic profile for SSc MØs, and demonstrated that co-culture of MØs with SSc dermal fibroblasts resulted in mutual activation of these cell types. However, the factors responsible for SSc MØ activation are unknown. In this regard, our new preliminary studies implicate SSc dermal fibroblast-derived exosomes as mediators of MØ activation in SSc. We show that uptake of SSc dermal fibroblast-derived exosomes induces profibrotic MØ activation. In addition, SSc fibroblast-activated MØs stimulate SSc fibroblast production of inflammatory cytokines and extracellular matrix (ECM) components. Therefore, we hypothesize that exosome-stimulated MØs and SSc fibroblasts engage in reciprocal activation. The goal of this study is to determine the mechanisms through which secreted fibroblast-derived exosomes and MØs promote fibrotic and inflammatory activation in SSc. We will define the molecular mechanisms, pathways, and key molecules that mediate cross-talk between fibroblast exosomes and MØs in SSc, and will test the therapeutic efficacy of targeting these regulators using a recently developed 3D human SSc skin model. Results of this work will provide the rational basis for the development of novel and effective treatments for SSc. The aims that will be tested in this application are: 1. Define fibroblast exosomal cargo and identify the components that regulate MØ activation in SSc. Genomic and molecular biology approaches will be used to identify the exosome mediators that induce SSc MØ activation and to identify the signaling pathways that underlie this activation. 2. Determine how exosomal-mediated changes in MØ activation promote inflammation and fibrosis in SSc. Co-culture studies demonstrate that SSc MØs induce activation of SSc fibroblasts, implicating a role for MØ-derived factors in the induction and maintenance of fibrosis. This aim will determine how SSc MØ activation impacts fibroblast activation.

抽象的全身性硬化症（SSC）是一种未知病因的慢性自身免疫性疾病，其特征是血管病，纤维化和炎症。 SSC无法治愈，很少有FDA批准的疾病 - 修改治疗。虽然成纤维细胞对疾病发展的贡献得到了广泛的认识，但最近研究表明，巨噬细胞（Møs）在SSC的发病机理中也起作用。在最近发表的工作中我们为SSCMøs开发了一种免疫表型，并证明了Møs的共同文化真皮成纤维细胞导致这些细胞类型的相互激活。但是，负责SSCMø的因素激活未知。在这方面，我们的新初步研究暗示SSC真皮成纤维细胞衍生外泌体作为SSC中Mø激活的介体。我们表明SSC皮肤成纤维细胞衍生的摄取外泌体诱导纤维化Mø激活。此外，SSC成纤维细胞激活的Møs刺激了SSC成纤维细胞炎性细胞因子和细胞外基质（ECM）成分的产生。因此，我们假设外部刺激的Møs和SSC成纤维细胞参与相互激活。这项研究的目标是为了确定分泌成纤维细胞衍生的外泌体和Møs促进纤维化的机制 SSC中的炎症激活。我们将定义分子机制，途径和关键分子在SSC中介导成纤维细胞外泌体和Møs之间的串扰，并将测试的治疗效率使用最近开发的3D人类SSC皮肤模型来针对这些调节剂。这项工作的结果将提供开发新颖和有效治疗SSC的理性基础。将在此应用程序是： 1。定义成纤维细胞外泌体货物并确定调节Mø激活的组件。基因组和分子生物学方法将用于识别影响的外泌体介体 SSCMø激活并确定该激活构成的信号通路。 2。确定外泌体介导的Mø激活的变化如何促进SSC的注射和纤维化。共培养研究表明，SSCMøs诱导SSC成纤维细胞激活，这暗示着对 Mø衍生的纤维化诱导和维持的因素。这个目标将决定SSCMø如何激活会影响成纤维细胞激活。