Role of TRPV4 mechanotransduction in foreign body response

TRPV4 机械传导在异物反应中的作用

• 批准号: 9365090
• 负责人: Shaik O Rahaman
• 金额: $ 43.56万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365090
• 关键词: Ablation; Adhesions; Affect; Atomic Force Microscopy; Attenuated; Biocompatible Materials; Biological Models; Bone Marrow; Bone Marrow Transplantation; Cell membrane; Cessation of life; Chronic; Collagen; Coupled; Data; Development; Devices; Disease; Encapsulated; Failure; Family; Fibrosis; Foreign Bodies; Foreign-Body Giant Cells; Gene Expression; Generations; Genetic; Goals; Human; Implant; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-4; International Aspects; Ion Channel; Lead; Link; Macrophage Activation; Mechanics; Mechanoreceptors; Mediating; Mediator of activation protein; Medical; Medical Device; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Organ; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphatidylinositols; Phosphotransferases; Procedures; Protein Isoforms; Regulation; Research; Role; Severities; Signal Transduction; Testing; Tissues; Traction; Vanilloid; base; cell motility; fibrogenesis; high throughput screening; implantation; in vitro Model; in vivo; inhibitor/antagonist; innovative technologies; insight; intraperitoneal; loss of function; macrophage; mechanotransduction; mortality; mouse model; novel; novel therapeutics; prevent; receptor; response; small molecule; subcutaneous

Implantable biomaterials and medical devices are used in millions of procedures each year worldwide. However, in large number of patients, the implantation of these 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 FBR consists of persistent inflammation coupled with fibrous encapsulation around the implant. There are no effective medical treatments. Hallmarks of the FBR include activation of macrophages at the tissue-implant interface, formation of destructive foreign body giant cells (FBGCs), and development of fibrous tissue that encapsulates the implant. The overall goal of our research is to understand the molecular mechanisms of the fibrotic response. Activated macrophages are thought to orchestrate the FBR by secreting inflammatory mediators. Emerging data support a critical role for a mechanical signal, e.g., substrate stiffness, in macrophage activation. However, a critical gap in this field is that the identity of the plasma membrane mechanosensor by which the mechanical signal is transduced/maintained is not known, nor are the downstream consequences of mechano-receptor signaling on the FBR. These gaps pose a significant barrier to progress in the field. In recent, exciting preliminary data, we obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family, and which is a known mechanosensor, may be the mediator of FBR. Specifically, we found that: 1) Trpv4 deletion in mice prevented macrophage accumulation, FBGC formation, and collagen accumulation in a subcutaneous implantation model; 2) the severity of the in vivo macrophage accumulation at the tissue-implant interface was dependent on the stiffness of the implant, and 3) genetic ablation or pharmacologic antagonism of TRPV4 blocked macrophage adhesion and spreading on stiff matrix, interleukin-4-induced FBGC formation, and inflammatory gene expression in both human and mouse bone marrow derived macrophages. Our preliminary data indicated that TRPV4 activity (Ca2+ influx) was augmented in response to increased matrix stiffness, and suggested that the molecular pathway linking TRPV4 activity to the FBR involved a specific phosphoinositide 3-kinase (PI3K) isoform, PI3K-alpha. The objective of this proposal is to determine the role of TRPV4 in the FBR. Based on our preliminary data, our central hypothesis is that TRPV4 mediates the FBR to biomaterials by increasing macrophage activation and fibrogenesis in a manner dependent on substrate stiffness and PI3K-alpha. We will utilize innovative technologies, in vivo and in vitro model systems, and a recently identified small molecule TRPV4 inhibitor to test the hypothesis with two Specific Aims. In Specific Aim 1 we will test the hypothesis that TRPV4 is a necessary component of the FBR in vivo; and in Specific Aim 2 we will test the hypothesis that mechanosensing by TRPV4 is a key component of the molecular mechanism of regulation of biomaterial- induced macrophage activation and fibrogenesis. When completed, we expect that the results of this study will generate novel information and insight regarding the mechanisms mediating the FBR to biomaterials, and will potentially identify a targetable receptor/pathway for the amelioration of FBR.

全世界每年有数百万例手术使用可植入生物材料和医疗器械。 然而，在大量患者中，这些装置的植入通常导致 异物反应（FBR）是一种慢性炎症状态，可最终导致植入物失效， 可能会对患者造成伤害或死亡。FBR由持续性炎症和纤维性炎症组成。 植入物周围的包封。没有有效的治疗方法。FBR的特点包括 组织-植入物界面巨噬细胞活化，形成破坏性异物巨细胞 （FBGC），以及包裹植入物的纤维组织的发育。我们研究的总体目标是 了解纤维化反应的分子机制。活化的巨噬细胞被认为 通过分泌炎症介质协调FBR。新兴数据支持一个关键角色， 机械信号，例如，基质硬度，巨噬细胞活化。然而，这一领域的一个关键差距是， 通过其转换/维持机械信号的质膜机械传感器的身份 目前还不清楚，也不是下游的机械受体信号传导的FBR的后果。这些差距 这对该领域的进展构成重大障碍。在最近令人兴奋的初步数据中，我们获得了证据， TRPV 4是瞬时受体电位香草素家族中的离子通道，并且其是已知的 机械感受器可能是FBR的介导者。具体来说，我们发现：1）小鼠中Trpv 4缺失阻止了 皮下植入中的巨噬细胞蓄积、FBGC形成和胶原蓄积 2）组织-植入物界面处体内巨噬细胞积聚的严重程度依赖于 对植入物硬度的影响，以及3）TRPV 4的基因消融或药理学拮抗作用被阻断 巨噬细胞在硬基质上的粘附和扩散，白细胞介素-4诱导的FBGC形成，以及炎症 人和小鼠骨髓来源的巨噬细胞中的基因表达。我们的初步数据显示 TRPV 4活性（Ca 2+内流）随着基质硬度的增加而增加，并提示， TRPV 4活性与FBR之间的分子通路涉及特异性磷酸肌醇3-激酶（PI 3 K） 亚型，PI 3 K-α。本提案的目的是确定TRPV 4在FBR中的作用。基于我们 根据初步数据，我们的中心假设是TRPV 4通过增加生物材料的FBR介导生物材料的FBR。 巨噬细胞活化和纤维化的方式依赖于底物硬度和PI 3 K-alpha。我们将 利用创新技术，体内和体外模型系统，以及最近发现的小分子 TRPV 4抑制剂来检验具有两个特定目的的假设。在具体目标1中，我们将检验以下假设： TRPV 4是体内FBR的必要组成部分;在具体目标2中，我们将检验以下假设： TRPV 4的机械传感是生物材料调节的分子机制的关键组成部分， 诱导巨噬细胞活化和纤维形成。完成后，我们预计这项研究的结果将 产生新的信息和洞察力的机制介导的FBR的生物材料，并将 潜在地鉴定用于改善FBR的靶向受体/途径。