Immunomodulatory Therapy for Bone Regeneration

炎症在骨形成、骨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的过程纠缠在一起。炎症信号的适当顺序和剂量对于适当的骨愈合至关重要。巨噬细胞是最早浸润骨折部位的细胞之一，由于它们促进成骨细胞分化和血管形成，因此对于骨折愈合是不可或缺的。此外，众所周知，机械条件影响骨折过程中骨痂的发育以及骨生成的类型和程度。但是，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物化学信号介导的激活上。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。我们的总体目标是阐明生物物理因素对巨噬细胞功能的影响，以开发一种免疫调节平台，减轻患者的骨疾病负担。 巨噬细胞通过肌动蛋白-细胞骨架重组、核变形和基因表达对细胞外基质力学变化作出反应。我们假设，生物物理力的形式，基板力学引发转录控制的巨噬细胞通过转录激活因子，MRTF-A，释放（在肌动蛋白聚合）和重新分配的细胞信号传导介质，HDAC 3（染色质压缩）。本项目的两个独立目标是：1）阐明小鼠骨折模型中巨噬细胞中肌动蛋白细胞因子介导的转录调控，2）设计具有合适粘弹性力学的免疫调节材料，以指导巨噬细胞的转录机制，以促进骨再生。 总的来说，我们提出的研究提供了对先天免疫反应在骨折愈合中的作用的见解，并开发了用于治疗性骨再生的下一代免疫调节材料。因此，我们的研究与CPRI COBRE的使命保持一致，以促进转化化学生物学研究，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.