权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10613579
负责人：
Patricia A. Pioli
金额：
$ 20.34万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613579
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 Macrophage Activation Maintenance Malignant Neoplasms Mediating Mediator Modeling Molecular Molecular Biology Myeloid Cell Activation Myeloid Cells Pathogenesis Pathway interactions Patients 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 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.

抽象的系统性硬化症（SSc）是一种病因不明的慢性自身免疫性疾病，其特征是血管病变、纤维化和炎症。 SSc 无法治愈，FDA 批准的疾病也很少—— 修改治疗方法。虽然成纤维细胞对疾病发展的贡献受到广泛认可，但最近研究表明巨噬细胞 (MØs) 在 SSc 的发病机制中也发挥着作用。在最近发表的作品中，我们开发了 SSc MØs 的免疫表型图谱，并证明 MØs 与 SSc 的共培养真皮成纤维细胞导致这些细胞类型的相互激活。然而，导致 SSc MØ 的因素激活未知。在这方面，我们新的初步研究表明 SSc 真皮成纤维细胞衍生外泌体作为 SSc 中 MØ 激活的介质。我们发现，真皮成纤维细胞来源的 SSc 的摄取外泌体诱导促纤维化 MØ 激活。此外，SSc 成纤维细胞激活的 MØs 刺激 SSc 成纤维细胞炎症细胞因子和细胞外基质（ECM）成分的产生。因此，我们假设外泌体刺激的 MØs 和 SSc 成纤维细胞参与相互激活。本研究的目标目的是确定分泌的成纤维细胞来源的外泌体和 MØs 促进纤维化的机制和 SSc 中的炎症激活。我们将定义分子机制、途径和关键分子介导 SSc 中成纤维细胞外泌体和 MØs 之间的串扰，并将测试其治疗效果使用最近开发的 3D 人类 SSc 皮肤模型来针对这些调节器。这项工作的结果将提供开发新的、有效的 SSc 治疗方法的合理基础。将测试的目标该应用程序是： 1. 定义成纤维细胞外泌体货物并确定调节 SSc 中 MØ 激活的成分。基因组和分子生物学方法将用于鉴定诱导的外泌体介质 SSc MØ 激活并确定该激活背后的信号通路。 2. 确定外泌体介导的 MØ 激活变化如何促进 SSc 中的炎症和纤维化。共培养研究表明，SSc MØs 诱导 SSc 成纤维细胞活化，暗示了 SSc 成纤维细胞的作用 MØ 衍生因子在纤维化的诱导和维持中的作用。这一目标将决定 SSc MØ 如何活化影响成纤维细胞活化。