Immunomodulatory Therapy for Bone Regeneration

炎症在骨形成、吸收和骨折愈合过程中起着至关重要的作用。骨折愈合的过程在生物学上与急性炎症和先天免疫过程纠缠在一起。适当的炎症信号序列和剂量对适当的骨愈合至关重要。巨噬细胞是最早渗透到骨折部位的细胞之一，它促进成骨细胞分化和血管形成，对骨折愈合是不可或缺的。此外，在骨折过程中，力学条件会影响骨痂的发育以及成骨的类型和程度。但在骨折愈合的背景下，大多数关于巨噬细胞反应的工作都集中在生化信号介导的激活上。骨折微环境的生物物理参数，特别是基质力学及其对巨噬细胞免疫表型的影响，在很大程度上被忽视了。我们的总体目标是阐明生物物理线索对巨噬细胞功能的影响，以开发一个减轻患者骨骼疾病负担的免疫调节平台。 巨噬细胞通过肌动蛋白-细胞骨架重组、核变形和基因表达来响应细胞外基质力学的变化。我们假设，底物力学形式的生物物理力通过转录激活因子MRTF-A、释放(在肌动蛋白聚合过程中)和细胞信号调节因子HDAC3(染色质压缩)来诱导巨噬细胞的转录控制。本项目的两个独立目标是：1)在小鼠骨折模型中阐明肌动蛋白细胞骨架介导的转录调控；2)设计具有合适粘弹性力学的免疫调节材料，以引导巨噬细胞的转录机制促进骨再生。 总体而言，我们提出的研究为先天免疫反应在骨折愈合中的作用提供了洞察力，并为治疗性骨再生开发了下一代免疫调节材料。因此，我们的研究与CPRI Cobre的使命非常一致，即促进翻译化学生物学研究，以推进治疗和战略，以应对重大的健康挑战。

Inflammation plays a vital role during bone formation, resorption, and fracture healing. The process of fracture healing is biologically entangled with that of acute inflammation and innate immunity. A proper sequence and dose of inflammatory signals are critical for proper bone healing. Macrophages, one of the first cells that infiltrate the fracture site, are indispensable for fracture healing as they promote osteoblastic differentiation and vascularization. Also, it is well recognized that mechanical conditions influence callus development and the type and extent of osteogenesis during fracture. But most work on the macrophage response, in the context of fracture healing, has focused on activation mediated by biochemical signals. The biophysical parameters of the fracture microenvironment, especially matrix mechanics and their influence on macrophage immunophenotypes, are largely overlooked. Our overall goal is to elucidate the influence of biophysical cues on macrophage function to develop an immunomodulatory platform reducing the burden of bone diseases in patients. Macrophages respond to changes in extracellular matrix mechanics through actin-cytoskeletal reorganization, nuclear deformation, and gene expression. We hypothesize that biophysical forces in the form of substrate mechanics elicit transcriptional control of macrophages via a transcriptional activator, MRTF-A, release (during actin polymerization) and redistribution of a cell signaling mediator, HDAC3 (chromatin compaction). The two independent aims for this project are: 1) Elucidate the actin cytoskeleton-mediated transcriptional control in macrophages in a murine fracture model, 2) Engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages to promote bone regeneration. Overall, our proposed research provides insights into the role of the innate immune response in fracture healing and develops next-generation immunomodulatory materials for therapeutic bone regeneration. Hence our research aligns well with the CPRI COBRE mission to facilitate translational chemical biology research to advance treatments and strategies to address significant health challenges.