Magnetic nanocomplexes-induced immunomodulation for fracture healing

磁性纳米复合物诱导的免疫调节促进骨折愈合

基本信息

批准号：
10372632
负责人：
Ramkumar Tiruvannamalai Annamalai
金额：
$ 19.22万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372632
关键词：
Actins Acute Adopted Area Biochemical Biocompatible Materials Biomechanics Bone Regeneration Bone Resorption Cells Chromatin Chronic Cues Cytoskeleton Defect Endothelium Engineering Exhibits Exogenous Factors Exposure to F-Actin Fostering Fracture Functional disorder G Actin Gene Expression Genes HDAC3 gene Immune response Infiltration Inflammation Inflammatory Response Injury Kinetics Lead Link Macrophage Activation Magnetism Metabolic Methodology Methods Modeling Morphology Multipotent Stem Cells Mus Natural regeneration Nuclear Nuclear Translocation Organ failure Osteogenesis Pathogenesis Pathology Peptides Pharmaceutical Preparations Phenotype Process Quality of life Regenerative Medicine Research Role Signal Transduction Site Specificity Surface TLR4 gene TNF gene Testing Therapeutic Therapeutic Intervention Tight Junctions Time Traction Transcriptional Regulation Trauma Traumatic injury Up-Regulation Work age related base bone bone fracture repair bone healing cancer imaging clinically translatable cyclooxygenase 2 density design diagnostic value disability immunomodulatory therapies immunoregulation inflammatory modulation insight iron oxide macrophage magnetic field nanocomplexes nanomaterials polymerization prevent regenerative therapy success systemic toxicity tissue regeneration transcription factor uptake wound healing

项目摘要

Non-healing fractures are a cause of severe disability and have devastating effects on the quality of life. Currently, there are no reliable first-line therapies that stimulate healthy bone formation and prevent nonunion. There is a growing body of evidence supporting the indispensable role of macrophages in fracture healing. Also, macrophage dysfunction is a critical component in the pathogenesis of non-healing or poorly healing fractures. Immunomodulatory strategies that apply biochemical factors are gaining traction to regulate macrophage phenotypes. However, they have limited success due to complications with specificity, efficacy, and systemic toxicity. Here we propose to develop a magnetic iron-oxide nanocomplexes (MNC)-based therapy for promoting fracture healing. The cytoskeletal dynamics of macrophages are intricately linked to their inflammatory response. Our studies confirmed that the cytoskeletal dynamics of macrophages are determined by their phenotype. Studies also show that mere manipulation of cytoskeletal dynamics using physical cues, without any exogenous factors, is shown to transform macrophage phenotype. This phenotype modulation is due to the nuclear translocation of the transcription factor MRTF-A, and changes in chromatin compaction caused by cytoplasmic-to-nuclear redistribution of histone deacetylase-3 (HDAC3). We hypothesize that intracellular magnetic force can elicit transcriptional control of macrophage phenotype and promote fracture healing via MRTF-A release and HDAC3 redistribution. In SA1, we will engineer magnetic nanocomplexes for targeted internalization and mechanistically elucidate intracellular force-induced modulation of the cytoskeleton and corresponding change in macrophage phenotype. In SA2, we will validate macrophage targeting of MNC and elucidate their therapeutic potential in a murine critical-sized femoral defect. The proposed research will be a paradigm shift in wound healing and will also provide crucial insights into the mechanobiology of macrophages that are valuable for diagnostic and therapeutic interventions.

不愈合的骨折会导致严重残疾，并对生活质量产生破坏性影响。目前，没有可靠的一线疗法可以刺激健康的骨形成并预防骨不连。越来越多的证据支持巨噬细胞在骨折愈合中不可或缺的作用。此外，巨噬细胞功能障碍是不愈合或愈合不良的发病机制的关键组成部分骨折。应用生化因子的免疫调节策略正在获得越来越多的关注来调节巨噬细胞表型。然而，由于特异性、有效性、和全身毒性。在这里，我们建议开发一种基于磁性氧化铁纳米复合物（MNC）的疗法，以促进骨折愈合。巨噬细胞的细胞骨架动力学与其炎症密切相关回复。我们的研究证实，巨噬细胞的细胞骨架动力学是由它们的表型。研究还表明，仅使用物理线索操纵细胞骨架动力学，无需任何外源因素都会改变巨噬细胞表型。这种表型调节是由于转录因子 MRTF-A 的核转位，以及由以下原因引起的染色质压缩的变化组蛋白脱乙酰酶 3 (HDAC3) 从细胞质到细胞核的重新分布。我们假设细胞内磁力可以引发巨噬细胞表型的转录控制并通过 MRTF-A 版本和 HDAC3 重新分发。在 SA1 中，我们将设计磁性纳米复合物，以实现靶向内化和机械化阐明细胞内力诱导的细胞骨架调节和巨噬细胞的相应变化表型。在 SA2 中，我们将验证 MNC 的巨噬细胞靶向性并阐明其治疗潜力小鼠临界尺寸股骨缺损。拟议的研究将是伤口愈合的范式转变，并将还提供了对巨噬细胞的机械生物学的重要见解，这对于诊断和治疗很有价值治疗干预。