Macrophage Depletion Therapy for Spinal Cord Injury

项目总结/摘要。脊髓损伤（SCI）是一种毁灭性的终身痛苦， 许多功能，包括运动、呼吸、自主调节和感觉/疼痛。不幸的是， 目前还没有FDA批准的SCI治疗方法。因此，翻译基础科学是一项迫切的需要 在实验室中开发的发现，在实验性SCI对人类 应用程序.脊髓损伤诱发了由常驻胶质细胞和浸润血液组成的椎管内炎症反应 白细胞尽管驻留和募集的免疫细胞亚群与CNS修复有关， 20多年来在不同SCI动物模型中的实验数据表明，急性单核细胞耗竭 (MD)始终具有神经保护作用。此外，有临床上可行的药物，如氯膦酸盐， 有效地消耗SCI后的单核细胞。然而，必须回答一些基本问题 在成功翻译之前，包括了解损伤水平对治疗的影响程度 有效性，以及了解MD对功能恢复和单核细胞的长期影响 再繁殖和命运因此，本提案的目标是审查长期和特定级别的职能 急性MD后的变化，使用临床相关结局，包括疼痛、自主神经反射异常、呼吸， 和前肢/手的功能。我们将研究急性脂质体包封氯膦酸盐治疗的效果， 在颈部和胸部SCI的啮齿动物模型中长达一年。具体而言，该赠款旨在：目标1：评估 急性MD对骨髓生成、生物分布和毒性的剂量反应效应;目的2：确定 急性MD对慢性SCI大鼠运动、感觉和自主神经功能恢复有效性。目标3： 确定急性MD对颈脊髓损伤后呼吸运动和前肢功能恢复的影响。 联合检查颈、胸段脊髓损伤后MD的影响， 关于单核细胞功能对感觉、自主神经、疼痛和 呼吸结果。氯膦酸二钠（又名二氯亚甲基二膦酸二钠）治疗的可行性 在SCI患者中，几乎在40年前就有报道，因此我们的建议是重要的，因为我们的数据来自于 这些研究可以适用于治疗人类SCI，并有望产生关键的转化影响。

PROJECT SUMMARY/ABSTRACT. Spinal cord injury (SCI) is a devastating lifelong affliction that impairs a number of functions including locomotion, breathing, autonomic regulation, and sensation/pain. Unfortunately, there is no current FDA approved therapy for SCI. Therefore, there is a critical need to translate basic science discoveries developed in the laboratory with promising effects after experimental SCI towards human application. SCI elicits an intraspinal inflammatory response comprised of resident glia and infiltrating blood leukocytes. Although subsets of resident and recruited immune cells have been implicated in CNS repair, more than 20 years of experimental data in different animal models of SCI indicate that acute monocyte depletion (MD) is consistently neuroprotective. Further, there are clinically viable drugs, such as clodronate, that can effectively deplete monocytes after SCI. However, a number of fundamental questions must be answered before successful translation including, understanding the extent to which injury level impacts therapeutic efficacy, as well as, understanding the long-term consequences of MD on functional recovery and monocyte repopulation and fate. Therefore, the goals of this proposal are to examine chronic and level-specific functional changes after acute MD using clinically relevant outcomes including pain, autonomic dysreflexia, respiration, and forelimb/hand function. We will study the effects of acute liposome encapsulated clodronate treatment for up to one year in rodent models of cervical and thoracic SCI. Specifically, this grant seeks to: Aim 1: evaluate the dose-response effects of acute MD on myelopoiesis, biodistribution, and toxicity; Aim 2: determine the efficacy of acute MD on recovery of locomotor, sensory, and autonomic function in chronic SCI rats. Aim 3: determine the effects of acute MD on recovery of respiratory motor and forelimb function after cervical SCI. The combined approach of examining the effects of MD after both cervical and thoracic SCI will provide unprecedented preclinical data regarding the effects of monocyte function on sensory, autonomic, pain, and respiratory outcomes. The feasibility of clodronate (aka disodium dichloromethylene diphosphonate) treatment in SCI individuals was reported almost 40 years ago therefore our proposal is significant as data from our studies could be adapted to treat human SCI and is expected to be of critical translational impact.