MCP-1 and attenuation of the foreign body response

描述(申请人提供)：生物材料引发炎症反应，导致破坏性异物巨细胞(FBGC)的形成，这些细胞参与包裹性异物反应(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，我们最近证实了在MCP-1缺失的巨噬细胞中基质金属蛋白酶(MMP9)-9的去调节作用，并证实了该酶在FBGC形成中的重要性。初步研究表明存在巨噬细胞融合机制，包括诱导基质金属蛋白酶-9和E-钙粘附素的表达。综上所述，我们对MCP-1缺失的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。在这一应用中，我们提出了一些研究，以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，我们的目标是将获得的一些知识转化为可行的生物工程策略，以减弱大脑中的FBR，并在新型藻酸盐支架的背景下进行。因此，本应用的具体目的是：1.测试MCP-1在FBR中的功能涉及调节巨噬细胞激活的假说；2.测试MCP-1参与脑FBR并调节神经炎症和BBB完整性的假说；3.测试FBGC形成中需要MCP-1涉及融合能力的巨噬细胞的激活并涉及诱导MMP-9和细胞表面相关的E-钙粘蛋白的假说；以及4.设计一种基于海藻酸盐的DNA递送大孔结构，旨在调节体内FBR的各个方面。 公共卫生相关性：将生物材料、设备和组织工程构建物植入血管化组织会引起炎症反应，从而导致植入失败。这种反应的一个特点是植入物表面的炎性细胞融合，形成可能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包裹，导致缺乏整合。在这一应用中，我们建议探索调节巨细胞形成的分子信号，并开发具有固有能力的生物材料，以调节它们引发的炎症反应。该项目的完成将使人们更好地了解活组织和生物材料之间的界面上的事件。

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.