Epigenetic regulation of macrophage response to biomaterial implants

巨噬细胞对生物材料植入物反应的表观遗传调控

• 批准号: 9918896
• 负责人: Timothy Lamont Downing
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-18 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918896
• 关键词: Acute; Adhesives; Adult; Biocompatible Materials; Biological Assay; Biology; Biopsy; California; Cell Shape; Cells; Chromatin; Chronic; Clinical; Clinical Treatment; Consent; Correlation Studies; Coupled; Cues; DNA; DNA Methylation; Disease; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Exposure to; Goals; Gossypium; Health; Healthcare; Hour; Human; Immune; Immune response; Impaired healing; Impaired wound healing; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Knowledge; Laboratories; Leucocytic infiltrate; Libraries; Liquid substance; Mammalian Cell; Mechanics; Mediator of activation protein; Medical center; Mesenchymal; Modification; Molecular; Operative Surgical Procedures; Outcome; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Polyurethanes; Polyvinyl Alcohol; Process; Property; Regulation; Research; Role; Saline; Sampling; Screening procedure; Shapes; Site; Small Interfering RNA; Structure; Surface; Testing; Tissues; Treatment Protocols; Vacuum; Veterans; Work; acute wound; base; cell type; chronic wound; cytokine; design; epigenetic regulation; epigenome; epigenomics; healing; high throughput screening; improved; in vivo; insight; macrophage; non-healing wounds; novel; novel strategies; novel therapeutics; pressure; response; scaffold; skin wound; small molecule; stem cells; therapeutic target; tissue regeneration; tissue repair; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy; wound; wound dressing; wound healing; wound treatment

PROJECT SUMMARY / ABSTRACT Impaired wound healing is a major clinical problem, and currently available treatment options often fail to fully repair tissue. Negative pressure wound therapy (NPWT) is a clinically used treatment that applies a biomaterial scaffold and negative pressure to mechanically stimulate dermal wounds. However, the mechanisms underlying NPWT remain poorly understood, and treatment still fails in a significant percentage of patients. Our previous work has established that topographical properties of biomaterials modulate the function of macrophages, essential innate immune cells that are involved in both advancing and resolving inflammation, and promoting tissue repair. More specifically, surfaces that cause macrophage elongation potentiate their response to wound healing cytokines, and protect cells from inflammation. Interestingly, cell elongation has been shown to cause profound changes in the epigenetic state of several cell types including stem cells and adult mesenchymal cells, but the role of epigenetics in biomaterial- induced macrophage polarization remains completely unknown. In this study, we propose to investigate the epigenetic regulation of macrophages in response to biomaterials structure during NPWT. We hypothesize that the structure of the biomaterial scaffold modulates the macrophage response through changes in the epigenome. We propose to test this hypothesis by: (1) investigating the effect of biomaterial structure on wound cytokines and cellular infiltrate in patients undergoing NPWT, and characterize the cellular transcriptomic and epigenomic landscapes, and (2) examine the effect of biomaterial structure on human macrophage polarization and epigenome in vitro, and screen the effects of a library of epigenetic modifiers on the biomaterial-induced macrophage response. The long-term goal of the proposed work is to better understand regulation of macrophages by the structure of biomaterials, in order to develop new strategies to promote wound healing and tissue regeneration.

项目总结/摘要 伤口愈合受损是一个主要的临床问题，目前可用的治疗方案 往往无法完全修复组织。负压伤口治疗（NPWT）是一种临床使用的 应用生物材料支架和负压进行机械刺激的治疗 皮肤伤口然而，对NPWT的机制仍然知之甚少， 治疗在相当大比例的患者中仍然失败。我们以前的工作已经确定， 生物材料的地形特性调节巨噬细胞的功能， 免疫细胞参与推进和解决炎症，并促进 组织修复更具体地说，引起巨噬细胞伸长的表面增强了它们的 它可以对伤口愈合细胞因子产生反应，并保护细胞免受炎症。有趣的是，Cell 已经证明，延伸引起几种细胞的表观遗传状态的深刻变化， 类型包括干细胞和成体间充质细胞，但表观遗传学在生物材料中的作用- 诱导的巨噬细胞极化仍然完全未知。在这项研究中，我们建议 研究巨噬细胞对生物材料结构的表观遗传调节， NPWT。我们假设生物材料支架的结构调节巨噬细胞 通过表观基因组的变化做出反应。我们建议通过以下方式来检验这一假设：（1） 研究生物材料结构对伤口细胞因子和细胞浸润的影响， 接受NPWT的患者，并表征细胞转录组和表观基因组 景观，和（2）研究生物材料结构对人类巨噬细胞的影响 极化和表观基因组体外，并筛选表观遗传修饰剂库的影响， 生物材料诱导的巨噬细胞反应拟议工作的长期目标是 更好地了解生物材料结构对巨噬细胞的调节，以便开发 促进伤口愈合和组织再生的新策略。