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.

非治疗裂缝是严重残疾的原因，对生活质量产生了毁灭性的影响。当前，尚无可靠的一线疗法来刺激健康的骨形成并防止骨不连。越来越多的证据支持巨噬细胞在断裂愈合中必不可少的作用。同样，巨噬细胞功能障碍是非愈合或愈合不佳的发病机理中的关键成分断裂。应用生化因素的免疫调节策略正在获得关注以调节巨噬细胞表型。但是，由于特异性，功效的并发症，他们的成功有限，和全身毒性。在这里，我们建议开发磁氧化铁纳米复合物（MNC）的促进治疗断裂愈合。巨噬细胞的细胞骨架动力学与它们的炎症无关回复。我们的研究证实，巨噬细胞的细胞骨架动力学取决于其表型。研究还表明，仅使用物理提示对细胞骨架动力学进行操纵，而没有任何外源性因素都显示出可以改变巨噬细胞表型。此表型调制是由于转录因子MRTF-A的核易位，以及由组蛋白脱乙酰基酶-3（HDAC3）的细胞质至核重新分布。我们假设细胞内磁力可以引起巨噬细胞表型的转录控制，并通过 MRTF-A释放和HDAC3重新分布。在SA1中，我们将设计磁性纳米复合物，以进行靶向内在化和机理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，并在A中阐明其治疗潜力鼠关键大小的股骨缺陷。拟议的研究将是伤口愈合的范式转变，将还提供对巨噬细胞机械生物学的关键见解，这些巨噬细胞对诊断和治疗干预措施。