Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossific

靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化

• 批准号: 10283122
• 负责人: Benjamin Levi
• 金额: $ 24.03万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283122
• 关键词: Targeting; Molecular; Cellular; Mediators; Inflammation

PROJECT SUMMARY Pathology stemming from excess ectopic bone formation, or trauma-induced heterotopic ossification (HO), presents a substantial barrier to recovery in 20% of patients with hip replacements, musculoskeletal trauma, spinal cord injury, amputations and burn injuries. Patients with HO experience chronic pain, restricted joint function, and open wounds; they often undergo surgical procedures to excise the offending bone, but these procedures fail to reverse the joint contractures and restricted range of motion. Even after a successful excision procedure, recurrence is common. With these current limitations in our understanding of HO and our inability to prevent its development, we set out to clarify the cells responsible and primary signaling pathways involved. Furthermore, we plan to validate a novel cell specific drug delivery system to block secretion of a primary ligand (Bone Morphogenetic Protein-2) from a primary cell (macrophage) responsible for inducing HO. Analysis of patients at high risk for HO and of our burn/tenotomy HO model have demonstrated an increase in Hypoxia Inducible Factor 1alpha (HIF-1) and Bone Morphogenetic Protein 2 (BMP2) signaling. However, where the BMP2 ligand originates and how to block its effect without causing off-target effects is unknown. Additionally, our data show that macrophages play a central role in HO and further studies are needed to elucidate how they are recruited and what ligands they secrete when they traffic to the injury site. The following aims are to test our hypothesis that that inhibition of mesenchymal cell HIF-1 mediated macrophage recruitment or inhibition of macrophage Bmp2 expression will prevent trauma-induced HO. Aim 1: To demonstrate that genetic loss of Hif1a reduces SDF1 production by mesenchymal cells and macrophage infiltration after injury. This aim will demonstrate that Hif-1α-mediated production of SDF-1 by mesenchymal cells at the injury site is responsible for macrophage recruitment immediately following injury. Aim 2: To define the role of macrophage recruitment and macrophage-specific production of BMP2 on HO. This aim will demonstrate that macrophage migration to the injury site and macrophage production of BMP2 is critical for ectopic mesenchymal cell chondrogenesis and heterotopic ossification. Aim 3: To demonstrate that novel microparticles can be used to silence genes specifically in macrophages. This aim will optimize microparticles for macrophage-specific uptake and drug delivery to administer Bmp2 siRNA.

项目概要 病理源于过度异位骨形成或创伤引起的异位骨化 (HO)，对 20% 进行髋关节置换术、肌肉骨骼的患者的康复构成重大障碍 HO 患者会经历外伤、脊髓损伤、截肢和烧伤等慢性疼痛和受限。 关节功能和开放性伤口；他们经常接受外科手术切除有问题的骨头，但是 即使成功后，这些手术也无法扭转关节结构和受限的运动范围。 由于目前我们对 HO 的理解存在局限性，因此复发很常见。 由于无法阻止其发展，我们着手阐明负责的细胞和主要信号传导途径 此外，我们计划验证一种新型细胞特异性药物输送系统，以阻止分泌。 来自负责诱导 H2O 的原代细胞（巨噬细胞）的初级配体（骨形态发生蛋白-2）。 对 HO 高危患者和我们的烧伤/跟腱切断术 HO 模型的分析表明， 缺氧诱导因子 1α (HIF-1α) 和骨形态发生蛋白 2 (BMP2) 信号传导增加。 然而，BMP2配体的起源以及如何阻断其作用而不引起脱靶效应仍然是一个问题。 此外，我们的数据表明巨噬细胞在 HO 中发挥核心作用，进一步的研究正在进行中。 需要阐明它们是如何被招募的以及它们在到达损伤部位时分泌的配体。 以下目的是检验我们的假设，即间充质细胞 HIF-1α 的抑制介导 巨噬细胞募集或抑制巨噬细胞 Bmp2 表达将预防创伤引起的 HO。 目标 1：证明 Hif1a 的遗传缺失会减少间充质细胞的 SDF1 产生，并且 损伤后巨噬细胞浸润 该目的将证明 Hif-1α 介导的 SDF-1 的产生。 损伤部位的间充质细胞负责在损伤后立即招募巨噬细胞。 目标 2：确定巨噬细胞募集和巨噬细胞特异性产生 BMP2 对 该目标将证明巨噬细胞迁移至损伤部位以及巨噬细胞的产生。 BMP2 对于异位间充质细胞软骨形成和异位骨化至关重要。 目标 3：证明新型微粒可用于沉默基因，特别是在 这一目标将优化巨噬细胞特异性摄取和药物递送的微粒。 施用 Bmp2 siRNA。