Investigate the mechanisms underlying microRNA-146a activity in regulation of foreign body response to biomaterials

研究 microRNA-146a 活性调节生物材料异物反应的机制

基本信息

批准号：
10641032
负责人：
Xiaoming He
金额：
$ 71.78万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-10 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641032
关键词：
Ablation Adhesions Affect Alginates Atomic Force Microscopy Biocompatible Materials Bone Marrow Cell fusion Cell physiology Cells Cessation of life Chronic Cicatrix Collagen Conditioned Reflex Cues Data Development Devices Diabetic mouse Disease Encapsulated Extracellular Matrix Failure Family Fibrosis Foreign Bodies Foreign-Body Giant Cells Gene Expression Generations Genetic Goals Human Hydrogels Implant Inflammation Inflammatory Ion Channel Islets of Langerhans Knock-out Knockout Mice Laboratories Link Macrophage Macrophage Activation Mediating Medical Medical Device MicroRNAs Microcapsules drug delivery system Modeling Molecular Morbidity - disease rate Mus Organ PIK3CA gene Pathogenesis Pathway interactions Patients Performance Phagocytosis Phosphatidylinositols Phosphotransferases Play Process Protein Isoforms Proteins Regulation Regulator Genes Reporting Research Role Severities Shapes TRPV channel Testing Tissues Traction Force Microscopy Untranslated RNA Vanilloid Work cell motility fibrogenesis implantation improved in vitro Model in vivo inflammatory marker insight intraperitoneal islet loss of function mechanical signal mechanical stimulus mechanotransduction mortality mouse model novel novel strategies receptor reconstitution response subcutaneous therapeutic miRNA therapeutically effective transcriptome sequencing

项目摘要

Project Summary Implantation of biomaterials and devices often leads to the development of a foreign body response (FBR), a chronic inflammatory condition that can ultimately lead to implant failure, which may cause harm to or death of the patient. The molecular mechanisms underlying the FBR remain poorly understood. Improved understanding of the molecular mechanisms underlying the generation of FBR is the most important step for the development of novel and effective therapeutic strategies that eliminate or reduce the FBR. Macrophages are central to development and progression of the FBR. They participate in the expression of inflammatory proteins, formation of destructive foreign body giant cells (FBGCs), remodeling of the extracellular matrix, and encapsulation of the implant. Emerging data support a critical role for a mechanical signal, e.g., matrix stiffness, in macrophage activation. MicroRNAs (miRs) are endogenous, small, non-coding RNAs that have emerged as powerful regulators of gene expression in numerous cellular processes including macrophage activation, cell fusion, inflammation, and fibrosis. The function of specific miRs in regulation of FBR to biomaterials is uncertain; specifically, it remains an open question whether matrix stiffness regulates miR expression to drive FBR. These gaps pose a significant barrier to progress in the FBR field. In recent, exciting preliminary data, we obtained evidence that miR-146a may be a negative regulator of FBR to biomaterials. Specifically, we found that: 1) miR-146a expression levels decreased in the implant-adhered tissues in a subcutaneous (s.c) implantation model, which correlated with increased macrophage accumulation, FBGC formation, and collagen accumulation; 2) miR-146a deletion in mice exacerbated FBR processes in a s.c implantation model; 3) the severity of the in vivo macrophage accumulation at the tissue-implant interface was dependent on the stiffness of the implant; 4) genetic ablation of miR-146a augmented macrophage adhesion and spreading on stiff matrix, FBGC formation, and inflammation in macrophages, and 5) genetic ablation of TRPV4, an ion channel in the transient receptor potential vanilloid family, inhibited development of implant-adhered tissue stiffness under FBR as determined by Atomic Force Microscopy. Further preliminary data suggested an association between matrix stiffness, miR-146a activity, and TRPV4, under FBR conditions. The objective of this proposal is to define the role of miR-146a in the FBR, and to elucidate the underlying molecular mechanisms. Based on our preliminary data, our central hypothesis is that miR-146a modulates the FBR to biomaterials by regulating macrophage activation and fibrogenesis in a manner dependent on implant-induced change in tissue stiffness. We will test our hypothesis through molecular gain- or loss-of-function studies. We expect that the results of this study may provide invaluable information and insight regarding the molecular mechanisms mediating the FBR to biomaterials, which may lead to the development of a novel and effective microRNA-based therapeutic strategy for the amelioration of the poorly understood FBR to biomaterials.

项目概要生物材料和设备的植入通常会导致异物反应（FBR）的发生，这是一种慢性反应最终可能导致植入失败的炎症状况，从而可能导致患者受伤或死亡。 FBR 背后的分子机制仍然知之甚少。加深对分子的理解 FBR产生的机制是开发新颖有效的药物的最重要的一步消除或减少 FBR 的治疗策略。巨噬细胞对于细胞的发育和进展至关重要 FBR。它们参与炎症蛋白的表达、破坏性异物巨体的形成细胞（FBGC）、细胞外基质的重塑和植入物的封装。新兴数据支持机械信号（例如基质刚度）在巨噬细胞激活中发挥关键作用。微小RNA (miR) 是内源性小非编码 RNA 已成为众多基因表达的强大调节因子细胞过程，包括巨噬细胞激活、细胞融合、炎症和纤维化。具体功能 miR 对 FBR 对生物材料的调节尚不确定；具体来说，矩阵是否存在仍然是一个悬而未决的问题刚度调节 miR 表达以驱动 FBR。这些差距对 FBR 领域的进展构成了重大障碍。最近，令人兴奋的初步数据表明，miR-146a 可能是 FBR 的负调节因子生物材料。具体来说，我们发现：1）植入物粘附组织中 miR-146a 表达水平下降皮下 (s.c) 植入模型，与巨噬细胞积累增加相关，FBGC 胶原蛋白的形成和积累； 2) 小鼠中 miR-146a 缺失加剧了皮下 FBR 过程植入模型； 3) 体内巨噬细胞在组织-植入物界面积聚的严重程度为取决于植入物的刚度； 4) miR-146a 的基因消融增强了巨噬细胞粘附和在坚硬基质上扩散、FBGC 形成和巨噬细胞炎症，以及 5) TRPV4（一种瞬时受体电位香草酸家族中的离子通道，抑制种植体粘附组织的发育由原子力显微镜测定的 FBR 下的刚度。进一步的初步数据表明存在关联 FBR 条件下基质硬度、miR-146a 活性和 TRPV4 之间的关系。该提案的目的是定义 miR-146a 在 FBR 中的作用，并阐明潜在的分子机制。基于我们的根据初步数据，我们的中心假设是 miR-146a 通过调节 FBR 来调节生物材料巨噬细胞的激活和纤维形成的方式依赖于植入物引起的组织硬度的变化。我们将通过分子功能获得或丧失的研究来检验我们的假设。我们期望这项研究的结果可能会提供有关介导 FBR 的分子机制的宝贵信息和见解生物材料，这可能会导致开发一种新颖且有效的基于 microRNA 的治疗策略对生物材料知之甚少的 FBR 的改进。