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.

项目摘要 病理学源于异位骨形成过多或创伤诱导的异位骨化 (HO)在20%的髋关节置换患者中， 创伤、脊髓损伤、截肢和烧伤。HO患者经历慢性疼痛，限制性 关节功能和开放性伤口;他们经常接受外科手术切除受伤的骨头，但 这些手术不能逆转关节挛缩和受限的活动范围。即使在成功的 切除手术，复发是常见的。由于我们目前对HO的理解存在这些局限性， 由于无法阻止其发展，我们着手阐明细胞的责任和主要信号通路 涉案此外，我们计划验证一种新的细胞特异性药物递送系统，以阻断分泌的细胞因子。 来自负责诱导HO的原代细胞（巨噬细胞）的原代配体（骨形态发生蛋白-2）。 对HO高风险患者和我们的烧伤/肌腱切断HO模型的分析表明， 缺氧诱导因子1 α（HIF-1 α）和骨形态发生蛋白2（BMP 2）信号传导增加。 然而，BMP 2配体的来源以及如何在不引起脱靶效应的情况下阻断其作用， 未知此外，我们的数据表明，巨噬细胞在HO中起着核心作用，进一步的研究是 需要阐明它们是如何被招募的，以及它们在运输到损伤部位时分泌什么样的配体。 下面的目的是验证我们的假设，即抑制间充质细胞HIF-1 β介导的 巨噬细胞募集或抑制巨噬细胞Bmp 2表达将防止创伤诱导的HO。 目的1：证明Hif 1a的遗传缺失减少间充质细胞产生SDF 1， 巨噬细胞浸润。这一目的将证明Hif-1α介导的SDF-1的产生是通过 损伤部位的间充质细胞负责在损伤后立即募集巨噬细胞。 目的2：确定巨噬细胞募集和巨噬细胞特异性产生BMP 2对 何这一目的将证明巨噬细胞向损伤部位的迁移和巨噬细胞产生 BMP 2对异位间充质细胞软骨形成和异位骨化至关重要。 目的3：证明新的微粒可用于特异性沉默基因， 巨噬细胞这一目标将优化用于巨噬细胞特异性摄取和药物递送的微粒， 施用Bmp 2 siRNA。