MCP-1 and attenuation of the foreign body response

描述（由申请人提供）：生物材料引发炎症反应，导致破坏性外源巨细胞（FBGC）的形成，参与包裹性异物反应（FBR）。我们已经发现趋化因子MCP-1是FBGC形成所必需的，并在FBR中发挥作用。此外，我们最近证实了基质金属蛋白酶(MMP)-9在mcp -1缺失的巨噬细胞中的失调，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诱导MMP-9和E-cadherin的表达。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具有广泛的组织特异性。在这个应用程序中，我们提出研究阐明巨噬细胞活化和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，以减弱大脑中的FBR和在新的海藻酸盐支架的背景下。因此，此应用程序的具体目的是：1。验证MCP-1在FBR过程中的功能涉及巨噬细胞活化的调节的假设；2. 验证MCP-1参与脑FBR并调节神经炎症和血脑屏障完整性的假设；3. 验证FBGC形成对MCP-1的需求涉及到融合能力巨噬细胞的激活和MMP-9和细胞表面相关E-cadherin的诱导这一假设；和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。

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.