Role of Wnt Signaling in Macrophage Response to Biomaterials

免疫系统调节对生物材料植入的初始反应，但哪些生物材料 控制炎症反应的特征尚不清楚。我们的长期目标是理解 先天免疫细胞在生物材料识别和炎症过程中使用的信号通路 促进组织愈合和再生。该提案的目标是确定WNT的角色 对生物材料表面特征、炎症反应和招募的反应中的信号转导 干细胞和免疫细胞。中心假说是巨噬细胞通过自分泌调节骨愈合。 Wnt配体的表型调节和分泌进入损伤微环境，调节 干细胞和免疫细胞的招募和活性。这项建议的基本原理是确定关键的WNT 可靶向调节和改善炎症过程的蛋白质和信号通路 这发生在生物材料植入后。拟议的工作还将确定关键的物理和化学物质 控制巨噬细胞激活和功能的生物材料表面的成分。中心假说 将通过三个目标进行测试：1)建立Wnt信号在巨噬细胞激活和释放中的作用 临床相关种植材料的炎症反应；2)建立自分泌和旁分泌效应 Wnt蛋白在巨噬细胞激活、巨噬细胞/间充质干细胞串扰和免疫细胞募集中的作用； 阐明生物材料表面巨噬细胞活化和分泌Wnt的机制 属性。我们将使用体外和体内研究相结合的方法来实现这些目标，条件是 巨噬细胞中Wnt信号通路的转基因敲除。巨噬细胞Wnt信号转导机制的研究 行为和作为炎症反应的协调者是创新的，在 生物材料植入的背景。拟议的工作意义重大，因为它将决定WNT的作用 巨噬细胞激活和炎性微环境产生中的蛋白质和信号。它是 同样重要的是，它将提供科学证据，证明WNT信号在 炎症环境，从长远来看，可以转化为其他领域，如慢性炎症 疾病和癌症。这项工作的最接近的预期结果是理解Wnt信号在 巨噬细胞活化及其在生物材料反应的炎症和愈合过程中的作用 表面特征。这项建议的结果将立即产生重要的积极影响 Wnt信号在巨噬细胞活化和炎症反应中的作用 调节这种激活和炎症反应。

The immune system modulates the initial response to biomaterial implantation, but which biomaterial characteristics control the inflammatory response is unknown. The long-term goal is to understand the signaling pathways used by innate immune cells in biomaterial recognition and inflammatory processes that lead to tissue healing and regeneration. The objective of this proposal is to determine the role of Wnt signaling in the response to biomaterial surface characteristics, inflammatory response, and recruitment of stem and immune cells. The central hypothesis is that macrophages regulate bone healing through autocrine phenotype modulation and secretion of Wnt ligands into the injury microenvironment, modulating the recruitment and activity of stem and immune cells. The rationale underlying this proposal is to identify key Wnt proteins and signaling pathways that can be targeted to modulate and ameliorate the inflammatory process that occurs after biomaterial implantation. The proposed work will also identify key physical and chemical components of biomaterial surfaces that control macrophage activation and function. The central hypothesis will be tested through three aims: 1) Establish the role of Wnt signaling in macrophage activation and inflammatory response on clinically relevant implant materials; 2) Establish the autocrine and paracrine effect of Wnt proteins in macrophage activation, macrophage/MSC crosstalk, and immune cell recruitment; 3) Elucidate the mechanism of macrophage activation and Wnt secretion in response to biomaterial surface properties. We will pursue these aims using a combination of in vitro and in vivo studies with conditional transgenic knockouts of Wnt signaling pathways in macrophages. The study of Wnt signaling on macrophage behavior and as an orchestrator of the inflammatory response is innovative and has not been explored in the context of biomaterial implantation. The proposed work is significant because it will determine the role of Wnt proteins and signaling in macrophage activation and the production of the inflammatory microenvironment. It is also significant because it will provide scientific evidence of the importance of Wnt signaling on the inflammatory milieu that can be translated in the long term into other areas such as chronic inflammatory diseases and cancer. The proximate expected outcome of this work is the understanding of Wnt signaling in macrophage activation and its contribution on the inflammatory and healing process in response to biomaterial surface characteristics. Results form this proposal will have important immediate positive impact establishing the role of Wnt signaling in macrophage activation and inflammatory response providing key targets for modulation of this activation and inflammatory response.