Targeting jmjd3 mitigates heterotopic ossification

靶向 jmjd3 可减轻异位骨化

• 批准号: 10441559
• 负责人: Katherine Ann Gallagher
• 金额: $ 60.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441559
• 关键词: Animal Model; Burn injury; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Data; Development; Disease; Elements; Enzymes; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Transcription; Heterotopic Ossification; Homeostasis; Human; Immune response; Inflammatory; Inflammatory Response; Injury; Interferon-beta; Interferons; JAK1 gene; Janus kinase; Kinetics; Laboratories; Lead; Mediating; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Modification; Molecular; Mus; Myelogenous; Normal tissue morphology; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Physical therapy; Physiologic Ossification; Preventive; Process; Production; Protocols documentation; Publishing; Regulation; Repression; Role; STAT protein; STAT3 gene; Secondary to; Signal Pathway; Signal Transduction; Site; Specificity; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Trauma; Treatment Efficacy; Work; base; bone; clinically relevant; combat; epigenetic regulation; experimental study; genetic approach; hip replacement arthroplasty; histone demethylase; histone modification; in vivo; inhibitor; injured; insight; macrophage; mouse model; musculoskeletal injury; nanoparticle; nanoparticle delivery; nanotherapeutic; nanotherapy; new therapeutic target; novel; osteochondral tissue; paracrine; pre-clinical; prevent; programs; promoter; repaired; stem cells; targeted treatment; therapeutic nanoparticles; therapy design; tissue repair; wound; wound healing

PROJECT SUMMARY/ABSTRACT Heterotopic ossification (HO) is the pathologic formation of extra-skeletal that is always preceded by an inflammatory insult and occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent or treat HO. In this regard, there is a void in our understanding of the molecular mechanisms underlying HO formation and progression. We present data that the histone demethylase, JMJD3, is increased in HO macrophages (Mφs) resulting in persistent production of transforming growth factor-beta (TGFꞵ1) at the HO injury site. This excess TGFꞵ1 causes aberrant mesenchymal progenitor cell (MPC) osteochondral ossification, resulting in HO formation. Further, using human cells and our experimental clinically relevant murine models of HO, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) / signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have led to our central hypothesis that IFNꞵ/JAK/STAT3 signaling directly increases Jmjd3 expression in HO tissue macrophages and that JMDJ3 increases macrophage Tgfb1 expression thus promoting aberrant MPC fate and HO formation. We further postulate that Mφ specific repression of JAK1/3 or JMJD3 and thus, TGFꞵ1 production using a novel targeted nanotherapy will halt HO formation and progression. As such, we propose the following aims: Aim 1: Elucidate the IFNꞵ1/JAK1/STAT3- mediated mechanism that regulates Mφ-specific JMJD3 expression in human and mouse HO wounds. Aim 2: Define the regulation of wound Mφ JMJD3 on TGFꞵ1 expression and the paracrine effects of Mφ JMJD3 on MPC fate under conditions of normal and aberrant wound healing (HO) in vivo. Aim 3: Examine the Mφ specificity and therapeutic efficacy and timing of Mφ-targeted JMJD3 and JAK1/3 nanoparticles on MPC phenotype and HO formation. In this translational project, our data will pave the way for the development of promising preventive nanotherapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ regulation of MPC fate and thereby prevent HO development following injury.

项目摘要/摘要 异位骨化（HO）是骨骼外骨骼的病理形成，始终是 髋关节置换术，烧伤或肌肉骨骼损伤后约20％的患者发生炎症损伤。 当前，尚无治疗或基于物理治疗的方案来预防或治疗HO。在这方面， 是我们对HO形成和进展的分子机制的理解的空隙。 我们列出的数据表明，HO巨噬细胞中的组蛋白脱甲基酶JMJD3增加了（Mφ），导致 在HO损伤部位持续产生转化生长因子-Beta（TGFꞵ1）。这超过了TGFꞵ1 引起异质祖细胞（MPC）骨软骨骨化，导致HO形成。 此外，使用人类细胞和我们的HO的实验临床相关鼠模型，我们已经确定 干扰素β（IFNβ）通过Janus激酶（JAK） /信号转录器和转录激活因子（STAT） 机理在MφS中诱导JMJD3。这些结果导致了我们的中心假设，即IFNꞵ/JAK/Stat3 信号传导直接增加HO组织巨噬细胞中的JMJD3表达，而JMDJ3增加了巨噬细胞 TGFB1表达，从而促进了异常的MPC命运和HO形成。我们进一步假设Mφ具体 抑制JAK1/3或JMJD3，因此，使用新型靶向纳米疗法的TGFꞵ1产生将停止HO 形成和进展。因此，我们提出以下目的：目标1：阐明IFNꞵ1/JAK1/STAT3- 调节人和小鼠HO伤口中Mφ特异性JMJD3表达的介导机制。目标2： 定义伤口MφJMJD3在TGFꞵ1表达和MφJMJD3对旁分泌效应上的调节 在体内正常和异常逻辑愈合（HO）的条件下，MPC命运。 AIM 3：检查Mφ特异性 MPC表型和MPC表型上的Mφ靶向JMJD3和JAK1/3纳米颗粒的治疗效率和时机 ho构造。在这个翻译项目中，我们的数据将为发展预防的发展铺平道路 针对介导Mφ调节的表观遗传酶的细胞特异性靶向的纳米治疗剂 MPC命运，从而防止受伤后HO发育。