MCP-1 and attenuation of the foreign body response

MCP-1和异物反应的衰减

基本信息

批准号：
8258805
负责人：
THEMIS R KYRIAKIDES
金额：
$ 33.59万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258805
关键词：
Activation Analysis Adhesions Alginates Angiogenesis Inhibitors Attenuated Biocompatible Materials Biomedical Engineering Blood - brain barrier anatomy Brain CCL2 gene Cell membrane Cell surface Cells Coupled DNA delivery Deposition Devices Dominant-Negative Mutation E-Cadherin Encapsulated Engineering Enzymes Event Exhibits Extracellular Matrix Extravasation Failure Foreign Bodies Gelatinase B Genes Giant Cells Implant In Vitro Inflammatory Inflammatory Response Investigation Knockout Mice Knowledge Lead Life Link Macrophage Activation Mediating Modeling Molecular Phenotype Play Process Recruitment Activity Role Signal Transduction Site Specificity Surface Testing Tissue Engineering Tissues Translating angiogenesis attenuation base chemokine design and construction implantation in vivo intraperitoneal macrophage molecular marker neuroinflammation novel plasmid DNA public health relevance response scaffold thrombospondin 2

项目摘要

DESCRIPTION (provided by applicant): Biomaterials elicit an inflammatory response leading to the formation of destructive foreign giant cells (FBGC) that participate in the encapsulating foreign body response (FBR). We have discovered that the chemokine MCP-1 is required for FBGC formation and plays a role in the FBR. In addition, we recently demonstrated deregulation of matrix metalloproteinase (MMP)-9 in MCP-1-null macrophages and confirmed the importance of this enzyme in FBGC formation. Preliminary studies suggest the existence of a macrophage fusion mechanism involving induction of MMP-9 and E-cadherin expression. Taken together, our investigation of MCP-1-null macrophages revealed numerous mechanistic links during the fusion of macrophages and showed that the FBR displays extensive tissue specificity. In this application we propose studies to elucidate the mechanism of macrophage activation and FBGC formation and identify molecular determinants of the FBR. In addition, we aim to translate some of the acquired knowledge into a feasible bioengineering strategy to attenuate the FBR in the brain and in the context of a novel alginate scaffold. Accordingly, the specific aims of this application are: 1. to test the hypothesis that the function of MCP-1 during the FBR involves modulation of macrophage activation; 2. to test the hypothesis that MCP-1 participates in the brain FBR and modulates neuroinflammation and the integrity of the BBB; 3. to test the hypothesis that the requirement for MCP-1 in FBGC formation involves the activation of fusion-competent macrophages and involves induction of MMP-9 and cell surface-associated E-cadherin.; and 4. to engineer an alginate-based DNA delivery macroporous construct designed to modulate various aspects of the FBR in vivo. PUBLIC HEALTH RELEVANCE: Implantation of biomaterials, devices, and tissue engineered constructs into vascularized tissues elicits an inflammatory response the can lead to implant failure. A hallmark of this response is the fusion of inflammatory cells on the implant surface to form multinucleated giant cells that can be destructive. In addition, the inflammatory response leads to the eventual encapsulation of the implant resulting in lack of integration. In this application we propose to explore the molecular signals that regulate the formation of giant cells and develop biomaterials with the inherent ability to modulate the inflammatory response they elicit. Completion of this project should lead to a greater understanding of the events at the interface between living tissues and biomaterials.

描述（由申请人提供）：生物材料引起炎症反应，导致破坏性外来巨细胞（FBGC）的形成，参与封装异物反应（FBR）。我们发现趋化因子 MCP-1 是 FBGC 形成所必需的，并在 FBR 中发挥作用。此外，我们最近证明了 MCP-1 缺失巨噬细胞中基质金属蛋白酶 (MMP)-9 的失调，并证实了该酶在 FBGC 形成中的重要性。初步研究表明巨噬细胞融合机制的存在涉及 MMP-9 和 E-钙粘蛋白表达的诱导。综上所述，我们对 MCP-1 缺失巨噬细胞的研究揭示了巨噬细胞融合过程中的许多机制联系，并表明 FBR 显示出广泛的组织特异性。在本申请中，我们提出研究来阐明巨噬细胞激活和 FBGC 形成的机制，并确定 FBR 的分子决定因素。此外，我们的目标是将一些获得的知识转化为可行的生物工程策略，以减弱大脑中和新型藻酸盐支架的 FBR。因此，本申请的具体目的是： 1. 检验 FBR 期间 MCP-1 的功能涉及巨噬细胞活化调节的假设； 2. 检验MCP-1参与大脑FBR并调节神经炎症和BBB完整性的假设； 3. 检验以下假设：FBGC 形成中对 MCP-1 的需求涉及具有融合能力的巨噬细胞的激活，并涉及 MMP-9 和细胞表面相关 E-钙粘蛋白的诱导。 4. 设计基于藻酸盐的 DNA 递送大孔构建体，旨在调节体内 FBR 的各个方面。公共健康相关性：将生物材料、装置和组织工程结构植入血管组织会引发炎症反应，从而导致植入失败。这种反应的一个标志是炎症细胞在植入物表面融合，形成具有破坏性的多核巨细胞。此外，炎症反应导致植入物最终被封装，导致整合不足。在本申请中，我们建议探索调节巨细胞形成的分子信号，并开发具有调节其引起的炎症反应的固有能力的生物材料。该项目的完成将使人们更好地了解活体组织和生物材料之间界面的事件。