Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury

项目总结 与皮肤和肌肉等其他组织不同，皮肤和肌肉能够完全重建组织，中央 神经系统(CNS)在受伤后缺乏适当愈合的能力。相反，中枢神经系统创伤修复的标志是 持续的胶质反应和疤痕组织沉积，所有这些都会因炎症而加剧。治疗性的 应用抗炎药物甲基强的松龙是目前治疗脊髓损伤的唯一选择 然而，脊髓损伤(SCI)只有急性疗效，不能解决组织重塑或疤痕形成。 本项目建议研究爱多拉明2，3-双加氧酶(IDO)作为一种新的免疫调节剂 治疗脊髓损伤。IDO之所以有吸引力，是因为它的双重靶向能力不仅能抑制促炎因素 而且还能促进促再生细胞表型，有效地恢复 中枢神经系统损伤后的炎症过程。这项研究的指导性假设是IDO将具有两面性 免疫调节对急性全身性炎症和缓解慢性驻留细胞激活的疗效 并在脊髓上留下疤痕。此外，该项目将调查IDO的两种创新的、功能化的形式 用于全身和局部免疫调节在脊髓损伤中的定向靶向。首先，用聚乙烯对IDO进行改性 脊髓损伤后立即全身静脉注射乙二醇组。聚乙二醇酯可改善蛋白质 血液稳定，循环时间延长，是全身给药的理想选择。PEG-IDO将 靶向循环中的白细胞以调节损伤后的早期炎症。其次，IDO与Galectin融合- 3(Gal3)是一种多糖结合蛋白，可增加组织靶点的局部滞留，将于一周内交付使用 损伤后评估对常驻细胞反应性、修复性免疫细胞存在和组织瘢痕形成的影响。 这种设计的基本原理是更好地利用IDO促进免疫修复机制的能力 病变部位周围局部存在的细胞和神经胶质细胞。IDO-Gal3与关键化合物的共给药 常驻神经胶质细胞直接产生神经保护代谢物(即KMO抑制剂)将进一步增强 局部性IDO的疗效观察结合在一起，这种结合将在一个新颖的、支持再生的 脱细胞神经支架协同减轻神经炎症。 总之，IDO的双重免疫调节潜力为抗炎药物提供了一个新的视角 对中枢神经系统损伤进行管理。拟议的工作将证明个人的新颖方法的优点 用于细胞特异性靶向的PEG-IDO和IDO-Gal3。长期目标是利用这种机械性的理解 作为研究开发更有效的中枢神经系统修复组合策略的第一步。

PROJECT SUMMARY Unlike other tissues, such as skin and muscle that are capable of complete tissue remodeling, the central nervous system (CNS) lacks the ability to properly heal after injury. Instead, CNS wound repair is marked by sustained glial reactivity and scar tissue deposition, all of which are exacerbated by inflammation. Therapeutic application of the anti-inflammatory methylprednisolone is the only current treatment option for spinal cord injury (SCI), however, it only has acute efficacy and does not resolve tissue remodeling or scarring. This project proposes to investigate idoleamine 2,3-dioxygenase (IDO) as a novel immunomodulatory therapeutic for SCI. IDO is attractive for its dual targeting ability not only to downregulate pro-inflammatory responses but also to promote pro-regenerative cell phenotypes, effectively restoring the imbalance of inflammatory processes after CNS injury. The guiding hypothesis of this research is that IDO will have dual efficacy in immunomodulation of acute systemic inflammation and mitigation of chronic resident cell activation and scarring in the spinal cord. Moreover, the project will investigate two innovative, functionalized forms of IDO for directed targeting of systemic and localized immunomodulation in SCI. First, IDO modified with polyethylene glycol (PEG) will be used for systemic intravenous administration immediately after SCI. PEG improves protein stability in blood and prolongs circulation time, making it an ideal candidate for systemic delivery. PEG-IDO will target circulating leukocytes to modulate early stage inflammation after injury. Secondly, IDO fused with galectin- 3 (Gal3), a glycan binding protein to increase local retention at a tissue target site, will be delivered one week after injury to evaluate effects on resident cell reactivity, reparative immune cell presence, and tissue scarring. The rationale for this design is to better harness IDO’s ability to promote reparative mechanisms in immune cells and glia that are locally present around the lesion site. Co-administration of IDO-Gal3 with key compounds that direct production of neuroprotective metabolites by resident glia (i.e., KMO inhibitors) will further enhance therapeutic effects of localized IDO. Together, this combination will be delivered within a novel, pro-regenerative decellularized neural scaffold to synergistically mitigate neuroinflammation. Overall, the dual immunomodulation potential of IDO provides a new perspective for anti-inflammatory drug administration for CNS injury. The proposed work will demonstrate merit for the individual novel approaches with PEG-IDO and IDO-Gal3 for cell-specific targeting. The long-term goal is to use this mechanistic understanding as a first step in research efforts to develop more effective combination strategies for CNS repair.