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

• 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
• 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

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.

项目摘要 生物材料和装置的植入通常导致异物反应（FBR）的发展，这是一种慢性炎症反应。 最终可能导致植入物失效的炎症性疾病，可能导致患者伤害或死亡。 FBR的分子机制仍然知之甚少。更好地理解分子 FBR的产生机制是开发新型有效的 消除或减少FBR的治疗策略。宏观经济是发展和进步的核心， FBR。它们参与表达炎性蛋白，形成破坏性的巨大异物 细胞（FBGCs）、细胞外基质的重塑和植入物的包封。新兴数据支持a 机械信号的关键作用，例如，巨噬细胞活化中的基质硬度。microRNAs（miRs） 内源性、小型、非编码RNA已成为许多基因表达的强大调节因子 细胞过程，包括巨噬细胞活化、细胞融合、炎症和纤维化。具体的功能 miRs在生物材料FBR调控中的作用尚不确定;具体而言，基质是否 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。 在最近令人兴奋的初步数据中，我们获得的证据表明miR-146 a可能是FBR的负调节因子， 生物材料具体地说，我们发现：1）miR-146 a在种植体粘附组织中的表达水平降低， 皮下（s.c）植入模型，与巨噬细胞蓄积增加相关，FBGC 2）小鼠中的miR-146 a缺失加剧了皮下注射中的FBR过程。 植入模型; 3）在组织-植入物界面处的体内巨噬细胞积聚的严重性是 4）miR-146 a的基因消融增强巨噬细胞粘附， 在硬基质上扩散、FBGC形成和巨噬细胞中的炎症，以及5）TRPV 4的基因消融， 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 FBR下的刚度，如通过原子力显微镜测定的。进一步的初步数据表明， 在FBR条件下，基质硬度、miR-146 a活性和TRPV 4之间的关系。这项建议的目的是 明确miR-146 a在FBR中的作用，并阐明其潜在的分子机制。基于我们 根据初步数据，我们的中心假设是miR-146 a通过调节FBR对生物材料的影响， 巨噬细胞活化和纤维化的方式依赖于植入物诱导的组织硬度的变化。我们 将通过分子功能获得或丧失的研究来验证我们的假设。我们希望这项研究的结果 可以提供关于介导FBR的分子机制的宝贵信息和见解， 生物材料，这可能导致开发一种新的和有效的基于microRNA的治疗策略， 对生物材料知之甚少的FBR的改进。

项目成果

Role of mechanosensitive channels/receptors in atherosclerosis.

机械敏感通道/受体在动脉粥样硬化中的作用。

• DOI: 10.1152/ajpcell.00396.2021
• 发表时间: 2022
• 期刊: American journal of physiology. Cell physiology
• 作者: Mukherjee,Pritha;Rahaman,SunehaG;Goswami,Rishov;Dutta,Bidisha;Mahanty,Manisha;Rahaman,ShaikO
• 通讯作者: Rahaman,ShaikO

Identification and functional analysis of a biflavone as a novel inhibitor of transient receptor potential vanilloid 4-dependent atherogenic processes.

• DOI: 10.1038/s41598-021-87696-9
• 发表时间: 2021-04-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Alharbi MO;Dutta B;Goswami R;Sharma S;Lei KY;Rahaman SO
• 通讯作者: Rahaman SO

TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization.

• DOI: 10.3389/fimmu.2020.570195
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Dutta B;Goswami R;Rahaman SO
• 通讯作者: Rahaman SO

Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation.

• DOI: 10.1074/jbc.ra120.014597
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Arya RK;Goswami R;Rahaman SO
• 通讯作者: Rahaman SO

Mechanosensing by TRPV4 mediates stiffness-induced foreign body response and giant cell formation.

• DOI: 10.1126/scisignal.abd4077
• 发表时间: 2021-11-02
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Goswami, Rishov;Arya, Rakesh K.;Sharma, Shweta;Dutta, Bidisha;Stamov, Dimitar R.;Zhu, Xiaoping;Rahaman, Shaik O.
• 通讯作者: Rahaman, Shaik O.