Immunomodulatory Therapy for Bone Regeneration

骨再生的免疫调节疗法

基本信息

批准号：
10368329
负责人：
Ramkumar Tiruvannamalai Annamalai
金额：
$ 23.31万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-08 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368329
关键词：
Actins Acute Address Biochemical Biological Biology Biophysics Bone Diseases Bone Regeneration Bone callus Cells Centers of Research Excellence Chemicals Chromatin Cues Cytoskeletal Modeling Cytoskeleton Development Dose Engineering Extracellular Matrix Fracture Fracture Healing Gene Expression Genetic Transcription Goals HDAC3 gene Health Immunophenotyping Inflammation Inflammatory Innate Immune Response Mechanics Mediating Mediator of activation protein Mission Modeling Mus Natural Immunity Nuclear Osteogenesis Patients Pharmacologic Substance Play Process Research Role Signal Transduction Site Therapeutic Transcription Coactivator Transcriptional Regulation Vascularization Work biophysical properties bone healing immunomodulatory therapies immunoregulation innovation insight macrophage next generation osteoblast differentiation polymerization response treatment strategy viscoelasticity

项目摘要

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.

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。炎症信号的正确顺序和剂量对于正确的骨愈合至关重要。巨噬细胞是最早浸润骨折部位的细胞之一，对于骨折愈合至关重要，因为它们促进成骨细胞分化和血管化。此外，众所周知，机械条件会影响骨折期间愈伤组织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研究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。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，以开发免疫调节平台，减轻患者骨疾病的负担。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剂 MRTF-A、细胞信号传导介质 HDAC3（染色质压缩）的释放（在肌动蛋白聚合期间）和重新分布来引发巨噬细胞的转录控制。该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骨架介导的转录控制，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，从而促进骨再生。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 的使命非常契合，即促进转化化学生物学研究，以推进治疗方法和策略，应对重大健康挑战。