Macrophage Depletion Therapy for Spinal Cord Injury

项目摘要/摘要。脊髓损伤(SCI)是一种毁灭性的终生痛苦，它损害了 一些功能，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批准的脊髓损伤治疗方法。因此，迫切需要翻译基础科学。 在对人类进行实验性脊髓损伤后，实验室发现的有希望的效果 申请。脊髓损伤引起的椎管内炎症反应，包括滞留的胶质细胞和渗入的血液 白细胞。尽管驻留和招募的免疫细胞亚群与中枢神经系统修复有关，但更多 20多年来在不同脊髓损伤动物模型上的实验数据表明，急性单核细胞枯竭 (MD)始终具有神经保护作用。此外，还有临床上可行的药物，如氯屈膦酸盐，可以 有效耗尽脊髓损伤后的单核细胞。然而，必须回答一些基本问题。 在成功翻译之前，包括了解损伤程度对治疗的影响程度 有效性，以及了解MD对功能恢复和单核细胞的长期后果 人口和命运。因此，这项建议的目标是检查慢性和特定级别的功能 根据临床相关结果，包括疼痛、自主神经反射障碍、呼吸、 前肢/手功能。我们将研究急性脂质体包裹的氯屈膦酸盐治疗慢性粒细胞白血病的效果 在颈部和胸部脊髓损伤的啮齿动物模型中，最长可达一年。具体地说，这笔赠款旨在：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对慢性脊髓损伤大鼠运动、感觉和自主神经功能恢复的影响。目标3： 确定急性MD对颈髓损伤后呼吸运动和前肢功能恢复的影响。 检查颈椎和胸部脊髓损伤后MD影响的联合方法将提供 关于单核细胞功能对感觉、自主神经、疼痛和 呼吸结果。氯屈磷酸钠(又名二氯亚甲基二膦酸二钠)治疗的可行性 在SCI中，个体是在近40年前报告的，因此我们的建议具有重要意义，因为来自我们的数据 研究可能适用于治疗人类脊髓损伤，并有望产生关键的翻译影响。

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.