Project 2 - Macrophage regulation of fibrosis and scarring during tissue regeneration

项目 2 - 组织再生过程中巨噬细胞对纤维化和疤痕的调节

• 批准号: 10437783
• 负责人: James W Godwin
• 金额: $ 28.81万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437783
• 关键词: Address; Adult; Aging; Animal Model; Antigens; Biological Assay; Biological Models; Brain; Carbohydrates; Cell Proliferation; Cells; Cessation of life; Cicatrix; Comparative Biology; Complex; Development; Disease; Enzymes; Epithelial; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Profile; Genes; Goals; Healthcare; Heart; Human; Immune; Infection; Infiltration; Injury; Innate Immune System; Label; Laboratories; Leukocytes; Limb structure; Liver; Lung; Mammals; Measures; Mediating; Mesenchymal; Methods; Modernization; Molecular; Myofibroblast; Natural regeneration; Operative Surgical Procedures; Organ; PTPRC gene; Patients; Pattern; Pharmacology; Phenotype; Play; Process; Protein-Lysine 6-Oxidase; Proteins; RNA Interference; Recovery of Function; Regulation; Role; Salamander; Signal Pathway; Signal Transduction; Site; Source; Spinal Cord; Surface; Testing; Time; Tissues; Traumatic injury; cell type; cellular targeting; crosslink; epithelial stem cell; gene network; healing; human tissue; innovation; insight; limb amputation; limb regeneration; macrophage; novel; overexpression; prevent; progenitor; programs; regenerative; regenerative therapy; repaired; therapy development; time use; tissue regeneration; tissue repair; tool; transcriptome sequencing; transdifferentiation; wound; wound healing

PROJECT 2 (Godwin) PROJECT SUMMARY The lack of scar-free healing and regeneration in humans imposes severe limitations on functional recovery after major traumatic injury, surgical interventions and disease. Default wound-repair in most adult human tissues initiates the formation of a protein/carbohydrate fibrotic network that progressively matures into dysfunctional scar tissue. In organs like the heart, lung and liver, formation of scar tissue can be deadly and contributes to ~45% of all U.S. deaths. Development of therapies that activate regeneration and scar-free repair programs in humans will transform modern healthcare. In contrast to humans and most other mammals, salamanders are capable of scar-free regeneration of almost all complex tissues including the limbs, heart, brain and spinal cord. Using the salamander as a model system, we recently demonstrated for the first time the critical role of the innate immune system in regulating scar-free regeneration. Specifically, we showed 1) that early infiltration of macrophages into damaged limb or heart tissue actively suppresses fibrosis and 2) that suppression of fibrosis is an essential step required for normal regeneration to occur. The cellular and molecular mechanisms by which macrophages suppress fibrosis after injury are completely unknown. The overarching goal of this proposal is to begin defining these mechanisms for the first time using salamander limb regeneration as a model system. Development of therapies that suppress fibrosis by modulating macrophage function may allow scar-free repair and regeneration of damaged tissues in humans. Our proposal will be the first to define how salamander macrophages suppress myofibroblast induction and scar tissue formation. We will use lineage tracing methods to identify the source of scar producing cells, which are the cellular targets of anti-fibrotic macrophage signaling. We will then define the macrophage subtypes that inhibit myofibroblast induction and fibrotic activation signals. Using RNA-sequencing, we will characterize gene expression patterns in macrophages that suppress myofibroblast induction. These studies will provide the first mechanistic insights into anti-fibrotic signaling pathways that allow macrophages to support scar-free healing. Finally, we will test the hypothesis that permanent scar tissue formation may be reversible by inhibition of lysyl oxidase, an enzyme that mediates crosslinking of the extracellular matrix, which, in turn, prevents scar-free healing and regeneration. This proposal is both significant and innovative as it will address a critical gap in our understanding of how fibrosis and scarring is overcome in a highly regenerative animal model. These new insights will form an essential step in the development of anti-fibrosis and pro-regenerative therapies for patients. !

项目 2（戈德温） 项目摘要 人类缺乏无疤痕愈合和再生，对功能造成严重限制 重大创伤、手术干预和疾病后的恢复。大多数成年人的默认伤口修复 人体组织启动蛋白质/碳水化合物纤维化网络的形成，该网络逐渐成熟为 功能失调的疤痕组织。在心脏、肺和肝脏等器官中，疤痕组织的形成可能是致命的 约占美国所有死亡人数的 45%。开发激活再生和无疤痕的疗法 人类修复计划将改变现代医疗保健。 与人类和大多数其他哺乳动物相比，蝾螈能够无疤痕再生 几乎所有复杂的组织，包括四肢、心脏、大脑和脊髓。以蝾螈为模型 系统，我们最近首次证明了先天免疫系统在调节中的关键作用 无疤痕再生。具体来说，我们表明 1) 巨噬细胞早期浸润到受损的肢体或 心脏组织积极抑制纤维化，并且 2) 抑制纤维化是实现纤维化所需的重要步骤 才能发生正常的再生。 巨噬细胞在损伤后抑制纤维化的细胞和分子机制是 完全未知。该提案的总体目标是开始定义这些机制 首次使用蝾螈肢体再生作为模型系统。开发治疗方法 通过调节巨噬细胞功能抑制纤维化可能使受损细胞无疤痕修复和再生 人体组织。 我们的提案将是第一个定义蝾螈巨噬细胞如何抑制肌成纤维细胞诱导的提案 和疤痕组织的形成。我们将使用谱系追踪方法来识别疤痕产生细胞的来源， 它们是抗纤维化巨噬细胞信号传导的细胞靶标。然后我们将定义巨噬细胞 抑制肌成纤维细胞诱导和纤维化激活信号的亚型。使用 RNA 测序，我们将 描述巨噬细胞中抑制肌成纤维细胞诱导的基因表达模式。这些研究 将为抗纤维化信号通路提供第一个机制见解，使巨噬细胞能够支持 无疤痕愈合。最后，我们将检验永久性疤痕组织形成可能是可逆的假设 通过抑制赖氨酰氧化酶，赖氨酰氧化酶是一种介导细胞外基质交联的酶，反过来， 防止无疤痕愈合和再生。 该提案既重要又具有创新性，因为它将解决我们理解中的一个关键差距 如何在高度再生的动物模型中克服纤维化和疤痕。这些新见解将 形成了开发患者抗纤维化和促再生疗法的重要一步。 ！