The Origin and Function of Macrophages in the Foreign Body Response

巨噬细胞在异物反应中的起源和功能

• 批准号: 9611776
• 负责人: Stephanie J Bryant
• 金额: $ 6.96万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9611776
• 关键词: Area; Attenuated; Biocompatible Materials; Biological; Biology; Blood; Cells; Chemistry; Chronic; Dimensions; Embryonic Development; Event; Exhibits; Fellowship; Fibrosis; Flow Cytometry; Foreign Bodies; Genes; Goals; Growth; Health; Hydrogels; Immune signaling; Immune system; Immunology; Implant; In Situ; Inflammation; Inflammatory; Injury; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Mediating; Mus; Musculoskeletal; Myeloid Cells; Outcome Study; Phenotype; Physicians; Population; Proliferating; Property; Regulation; Research; Research Training; Role; Scientist; Signal Pathway; Site; Source; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Transgenic Mice; Work; capsule; design; discrete time; experimental study; follower of religion Jewish; healing; immunoregulation; improved; improved outcome; injured; insight; macrophage; monocyte; mouse model; negative affect; novel; novel strategies; novel therapeutics; prevent; recruit; response; sabbatical; scaffold; self-renewal; time interval

Synthetic hydrogels are remarkable platforms for in situ cell delivery in a three-dimensional scaffold where the chemistry and properties can be tuned to promote and facilitate tissue growth. Synthetic hydrogels, however, as with any non-biological material, suffer from the immune system’s normal response to foreign materials. The foreign body response (FBR) is characterized by chronic inflammation and the formation of a dense, avascular fibrous capsule. These events can negatively affect cells embedded within a hydrogel and create a barrier between the scaffold and the host tissue that prevents integration. Given that synthetic hydrogels offer numerous advantages for designing tunable scaffolds (e.g., material stiffness, degradation rates, etc.), a better understanding of the FBR is needed. While macrophages are known to orchestrate the FBR, our current view of macrophages in the FBR is oversimplified. Fundamentally, these has been a recent paradigm shift in how macrophages are viewed. We now know that macrophages from distinctly different origins, “resident” tissue macrophages and “recruited” macrophages from blood-derived monocytes, respond to areas of injury, but with distinctly different roles. “Recruited” monocyte-derived macrophages are thought to be the main drivers of pro- inflammatory and pro-fibrotic responses in injured tissue. Thus, it is reasonable to postulate that these different macrophage populations may be involved in the FBR. The overarching goal of this senior fellowship is to apply this new paradigm to study the macrophage in the context of the FBR. This idea that macrophages, which accumulate at the site of an implant, arrive from different origins has not been considered previously in the FBR. These studies are central to the research training plan that will broaden the PI’s knowledge in immunology, enable her to learn state-of-the-art techniques to study macrophages, and facilitate the PI’s transition to establish a new research direction in immunology of biomaterials for musculoskeletal research. The overarching hypothesis for this project is that “recruited” macrophages from blood-derived monocytes are primarily responsible for the events that lead to chronic inflammation and fibrosis in the FBR. To test this hypothesis two specific aims are proposed: a) identify the biological effect of macrophages and their functional state on the FBR using CCR2 knockout mouse models and b) identify the temporal biological effect of macrophages and their functional state on the FBR using MaFIA transgenic mouse models. We will employ novel techniques and mouse models that prevent recruitment of monocyte-derived (i.e., “recruited”) macrophages (i.e., CCR2 knockouts) and that allow us to inducibly deplete all macrophages at discrete time intervals (i.e., MaFIA). The outcome of these studies is to re-define the macrophage in the context of the FBR and importantly identify how different macrophage subpopulations contribute to the FBR. This new insight will be leveraged to design immunomodulatory hydrogels that target the timing and the macrophage subpopulation(s) that is responsible for the FBR.

合成水凝胶是在三维脚手架中进行原位细胞输送的显着平台 可以调整化学和特性以促进和促进组织生长。但是，合成水凝胶为 有了任何非生物材料，免疫系统对异物的正常反应都受到影响。 异物反应（FBR）的特征在于慢性炎症和致密的疾病的形成 纤维囊。这些事件可能会对嵌入水凝胶中的细胞产生负面影响，并产生屏障 在脚手架和宿主组织之间阻止整合。鉴于合成水凝胶提供了许多 设计可调脚手的优点（例如，材料刚度，降解率等），更好 需要了解FBR。虽然众所周知巨噬细胞可以编排FBR，但我们目前的观点 FBR中的巨噬细胞过于简单。从根本上讲，这些是最近的范式转变 查看了巨噬细胞。我们现在知道，巨噬细胞来自截然不同的起源，“居民”组织 巨噬细胞和来自血液衍生的单核细胞的巨噬细胞对损伤区域有反应，但有 截然不同的角色。 “被招募”单核细胞衍生的巨噬细胞被认为是促进的主要驱动力 受伤组织中的炎症和促纤维化反应。那是合理地假设这些不同的 FBR可能涉及巨噬细胞种群。这个高级奖学金的总体目标是 在FBR的背景下，应用这种新范式研究巨噬细胞。这个巨噬细胞的想法， 在植入物的位置积聚，从不同的起源到达，以前尚未在FBR中考虑。 这些研究是研究培训计划的核心，该计划将扩大PI的免疫学知识， 使她能够学习最先进的技术来研究巨噬细胞，并促进PI的过渡以建立 肌肉骨骼研究的生物材料免疫学的新研究方向。总体 该项目的假设是从血液衍生的单核细胞中的“招募”巨噬细胞是主要的 负责导致慢性感染和FBR纤维化的事件。测试这两个假设两个 提出了具体目的：a）确定巨噬细胞及其功能状态对FBR的生物学作用 使用CCR2敲除小鼠模型，b）确定巨噬细胞的暂时生物学效应及其 使用黑手党转基因小鼠模型在FBR上的功能状态。我们将采用新颖的技术和鼠标 防止单核细胞衍生（即“招募”）巨噬细胞（即CCR2敲除）和 这使我们能够以离散的时间间隔（即黑手党）诱导所有巨噬细胞减去所有巨噬细胞。这些结果 研究是在FBR的背景下重新定义巨噬细胞，并重要地确定如何不同 巨噬细胞亚群有助于FBR。这种新的见解将被利用 针对时间和巨噬细胞亚群的免疫调节水凝胶，负责 FBR。