Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI

激素干预保护轴突髓磷脂，促进 SCI 功能恢复

• 批准号: 10291814
• 负责人: NAREN L BANIK
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291814
• 关键词: Acute; Animal Model; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Attenuated; Axon; Biological Availability; Calcium Signaling; Cell Differentiation process; Cell Maturation; Cells; Chronic; Cicatrix; Clinical; Clinical Trials; Data; Dose; Drug Delivery Systems; Epithelial; Estrogens; Exposure to; Extracellular Matrix; Fibroblasts; Formulation; Gait; General Population; Glial Fibrillary Acidic Protein; Gliosis; Goals; Grant; Growth Factor; Hormonal; Hormones; Human; Immune; In Vitro; Inflammation; Inflammatory; Injections; Injury; Intervention; Lesion; Methylprednisolone; Microglia; Modeling; Myelin; Natural regeneration; Neuroglia; Neurons; Neuroprotective Agents; Oligodendroglia; Phase; Pilot Projects; Plasma; Production; Rattus; Recovery of Function; Regenerative capacity; Route; Safety; Sepharose; Signal Transduction; Spinal Cord; Spinal cord injury; T cell response; Techniques; Testing; Th1 Cells; Therapeutic; Therapeutic Agents; Tissues; Translations; Treatment Efficacy; Vascular Endothelial Growth Factors; Veterans; Vimentin; angiogenesis; established cell line; estrogenic; functional improvement; glial cell-line derived neurotrophic factor; immunoregulation; improved; medication safety; myelination; nano; nanoparticle; nanoparticle delivery; neuroprotection; novel; novel marker; novel strategies; oligodendrocyte precursor; precursor cell; preservation; primary endpoint; protective effect; side effect; therapeutically effective; tissue regeneration

Estrogen (E2) treatment is known to be neuroprotectant in spinal cord injury (SCI). This hormone is highly pleiotropic and has been shown to decrease apoptosis, modulate calcium signaling, regulate growth factor expression, act as an anti-inflammatory, and can drive angiogenesis. These beneficial effects were found at the low dose of 10μg/kg E2 (multiple i.v. injections; previous grant), which helped in obtaining IND approval for taking this into a small clinical safety trial. However, the dose remains non-physiologic and thereby poses a safety hurdle for clinical use. The emergence of smart drug delivery techniques, such as nanoparticles, may allow for increased drug safety and improved efficacy. Thus, the goal of this study is to investigate the effects of nanoparticle delivery of lower doses of E2 (2.5-5.0µg, single dose) that may avoid the high systemic exposures seen with traditional dose routes (i.v. or i.p.) and allow for enhanced protective and reparative effects on lesioned tissue. Preliminary data show that a single administration of rapid release formulated PLGA-PEG nanoparticles loaded with E2 can focally deliver E2 to the contused spinal cord with reduced plasma concentrations when compared with i.v. dosing and can drive estrogenic changes. Additionally, this approach has shown that a single 5.0µg dose of nanoparticle E2 (N-E2) can improve locomotor function recovery. Pilot data suggest that E2 supports the survival of oligodendrocyte precursor cells (OPC) when exposed to toxic factors from Th1 cells and microglia in vitro. Thus, using a cocktail of rapid and slow release nanoparticle formulations, an entirely novel approach, enhanced efficacy may be achieved after SCI. This approach may allow for rapid translation of this known neuroprotectant into clinical trials. We hypothesize that focal delivery of estrogen via nanoparticles will minimize plasma exposure and increase tissue concentrations thereby allowing for maximized therapeutic potential in SCI. To test the hypothesis, three specific aims are proposed: (1) Examine N-E2 release profile and estrogenic effects on inflammation, gliosis, and neuronal protection in acute SCI; (2) Determine the mechanisms of E2-driven protective effects on epithelial, glial and neuronal cells following slow release N-E2 in acute and chronic SCI; and (3) Investigate the potential additive effects of rapid and slow release N-E2 on reduced glial scarring, enhanced regeneration, and improved locomotor function in chronic SCI. Completion of this study will identify the optimal dosing strategy of E2 loaded nanoparticles for delivery of this therapeutic agent in SCI. Additionally, as novel targets of E2 signaling are explored, progress in understanding the mechanisms of estrogenic driven neuroprotection will be made. These data should provide sufficient evidence to support the translation of E2 into clinical trials, with the ultimate goal of providing a safe and effective therapeutic to treat both veterans and the general population suffering from SCI.

雌激素(E_2)治疗对脊髓损伤(SCI)具有神经保护作用。这种荷尔蒙含量很高 多效性，已被证明可减少细胞凋亡，调节钙信号，调节生长因子 表达，起到抗炎的作用，并能促进血管生成。这些有益的影响可在 小剂量10μg/kg雌二醇组(多次静脉注射)。注射；以前的赠款)，这有助于获得IND对 将其带入一项小型临床安全试验。然而，剂量仍然是非生理性的，因此会造成 临床使用的安全障碍。智能药物输送技术的出现，如纳米颗粒，可能会 考虑到提高药物安全性和改善疗效。因此，本研究的目的是调查这些影响 较低剂量(2.5-5.0微克，单剂)的E2纳米粒传递，可避免高系统性 传统剂量途径所见的暴露(静脉注射)或I.P.)并允许加强保护和修复 对受损组织的影响。初步数据显示，单次给药速释制剂 载雌二醇的PLGA-聚乙二醇纳米粒可将雌二醇局灶性输送到脊髓挫伤处 与静脉注射比较时的血浆浓度。剂量，并可推动雌激素的变化。此外，这一点 一种方法表明，单次注射5.0微克的纳米E2(N-E2)可以改善运动功能 恢复。初步数据表明，在以下情况下，E2支持少突胶质前体细胞(OPC)的存活 体外暴露于Th1细胞和小胶质细胞的毒性因子。因此，使用快速和缓慢释放的鸡尾酒 纳米颗粒制剂，一种全新的方法，在脊髓损伤后可能获得增强的疗效。这 这种方法可能会使这种已知的神经保护剂迅速转化为临床试验。我们假设 通过纳米颗粒集中传递雌激素将最大限度地减少血浆暴露并增加组织 浓度，从而允许最大限度地治疗脊髓损伤的潜力。为了检验这一假设，有三个 具体目标被提出：(1)检测N-E_2释放谱和雌激素对炎症、胶质增生、 以及对急性脊髓损伤的神经元保护作用；(2)确定雌激素对大鼠脊髓损伤的保护作用机制 急慢性脊髓损伤中N-E_2缓释对上皮细胞、神经胶质细胞和神经细胞的影响 快速和缓释N-E2在减少胶质瘢痕形成、促进再生和 改善慢性脊髓损伤患者的运动功能。这项研究的完成将确定最佳给药策略 用于脊髓损伤治疗的E2载药纳米粒。此外，作为E2的新靶点， 对信号转导进行了探索，对雌激素驱动的神经保护机制的理解将取得进展 制造。这些数据应该提供足够的证据来支持将E2转化为临床试验， 最终目标是为退伍军人和普通民众提供安全有效的治疗方法 患有脊髓损伤。