Macrophage Depletion Therapy for Spinal Cord Injury

巨噬细胞耗竭疗法治疗脊髓损伤

• 批准号: 10533341
• 负责人: Warren Joseph Alilain
• 金额: $ 62.2万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533341
• 关键词: Acute; Affect; American; Animal Model; Animals; Anti-Inflammatory Agents; Applications Grants; Autonomic Dysreflexia; Basic Science; Biodistribution; Biological Assay; Bone Marrow; Breathing; Caring; Cell Death; Cells; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Clinical Trials; Congresses; Contusions; Data; Dichloromethylene Diphosphonate; Distal; Dose; Encapsulated; Esthesia; FDA approved; Flow Cytometry; Forelimb; Frustration; Funding; Goals; Grant; Hand functions; Hindlimb; Hour; Human; Immune; Immune Targeting; Immunologic Deficiency Syndromes; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lesion; Leukocytes; Liposomes; Liver; Locomotion; Locomotor Recovery; Macrophage; Mediating; Minocycline; Modeling; Modification; Motor; Multiple Trauma; Myelopoiesis; Neuroglia; Organ; Outcome; Outcome Measure; Output; Pain; Pathology; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Production; Publishing; Quality of life; Rattus; Recovery; Recovery of Function; Regulation; Reporting; Research; Research Personnel; Respiration; Rodent; Rodent Model; Sensory; Site; Spinal Cord; Spinal Cord Contusions; Spinal Cord Plasticity; Spinal Injuries; Spinal cord injury; Spleen; Steroids; Testing; Therapeutic; Thoracic spinal cord structure; Time; Tissues; Toxic effect; Translating; Translations; Treatment Efficacy; United States; United States National Institutes of Health; Voice; arm; axonal sprouting; central pattern generator; clinically relevant; efficacy evaluation; functional disability; functional outcomes; improved; improved outcome; indexing; innovation; meetings; monocyte; neuroprotection; novel therapeutic intervention; pre-clinical; preclinical evaluation; recruit; repaired; respiratory; response; side effect; synaptogenesis; tissue repair; translational impact; translational therapeutics

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.

项目摘要/摘要。脊髓损伤 (SCI) 是一种毁灭性的终生痛苦，会损害患者的身体健康 多种功能，包括运动、呼吸、自主调节和感觉/疼痛。很遗憾， 目前 FDA 尚无批准的 SCI 治疗方法。因此，迫切需要翻译基础科学 在对人类进行 SCI 实验后，实验室取得的发现具有良好的效果 应用。 SCI 引发由常驻神经胶质细胞和浸润血液组成的椎管内炎症反应 白细胞。尽管常驻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多年来不同SCI动物模型的实验数据表明，急性单核细胞耗竭 (MD) 始终具有神经保护作用。此外，还有临床上可行的药物，例如氯膦酸盐，可以 有效消除 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，包括了解伤害程度影响治疗的程度 功效，以及了解 MD 对功能恢复和单核细胞的长期影响 重新人口和命运。因此，该提案的目标是检查慢性和特定水平的功能 急性 MD 后的变化使用临床相关结果，包括疼痛、自主神经反射异常、呼吸、 和前肢/手功能。我们将研究急性脂质体封装的氯膦酸盐治疗的效果 在颈椎和胸部 SCI 啮齿动物模型中，效果长达一年。具体来说，这笔赠款旨在： 目标 1：评估 急性MD对骨髓细胞生成、生物分布和毒性的剂量反应效应；目标 2：确定 急性MD对慢性SCI大鼠运动、感觉和自主功能恢复的功效。目标 3： 确定急性 MD 对颈椎 SCI 后呼吸运动和前肢功能恢复的影响。 检查颈椎和胸部 SCI 后 MD 效果的综合方法将提供 关于单核细胞功能对感觉、自主神经、疼痛和神经的影响的前所未有的临床前数据 呼吸系统结果。氯膦酸盐（又名二氯亚甲基二膦酸二钠）治疗的可行性 大约 40 年前就报道了 SCI 个体中的情况，因此我们的建议非常重要，因为我们的数据来自 研究可用于治疗人类 SCI，预计将产生重要的转化影响。