Macrophage Depletion Therapy for Spinal Cord Injury

巨噬细胞耗竭疗法治疗脊髓损伤

• 批准号: 10208026
• 负责人: Warren Joseph Alilain
• 金额: $ 63.93万
• 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/10208026
• 关键词: Acute; Affect; American; Americas; Animal Model; Animals; Anti-Inflammatory Agents; Applications Grants; Autonomic Dysreflexia; Basic Science; Biodistribution; Biological Assay; Bone Marrow; Breathing; Cell Death; Cells; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Clinical Trials; Congresses; Contusions; Data; Dichloromethylene Diphosphonate; Distal; Dose; Encapsulated; FDA approved; Flow Cytometry; Forelimb; Frustration; Funding; Goals; Grant; Hand functions; Hindlimb; Hour; Human; Immune; Immune Targeting; Immunologic Deficiency Syndromes; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lead; Lesion; Leukocytes; Liposomes; Liver; Locomotion; Locomotor Recovery; Mediating; Minocycline; Modeling; Modification; Motor; Multiple Trauma; Myelopoiesis; Neuroglia; Organ; Outcome; Outcome Measure; Output; Pain; Pathology; 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; Visceral pain; Voice; arm; axonal sprouting; base; care outcomes; central pattern generator; clinically relevant; functional disability; functional outcomes; improved; improved outcome; indexing; innovation; macrophage; meetings; monocyte; novel therapeutic intervention; pain sensation; pre-clinical; preclinical evaluation; recruit; repaired; respiratory; response; side effect; synaptogenesis; tissue repair; translational impact

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）是一种破坏性的终身痛苦，会损害 功能，呼吸，自主神经调节和感觉/疼痛的功能数量。很遗憾， 目前尚无FDA批准的SCI疗法。因此，迫切需要翻译基础科学 实验室中开发的发现具有实验性SCI后对人类的有希望的影响 应用。 SCI引起了由常驻神经胶质和浸润的血液组成的主要炎症反应 白细胞。尽管居民和招募的免疫细胞的亚集已与中枢神经系统维修有关，但更多 SCI的不同动物模型中的20年实验数据表明急性单核细胞耗竭 （MD）始终是神经保护性的。此外，还有临床上可行的药物，例如克罗德膦酸盐，可以 SCI后有效耗尽单核细胞。但是，必须回答许多基本问题 在成功翻译之前，包括了解伤害水平影响治疗的程度 有效性以及理解MD在功能恢复和单核细胞的长期后果 重生和命运。因此，该提案的目标是检查慢性和特定水平的功能 急性MD后使用临床上相关的结果后发生变化 和前肢/手功能。我们将研究急性脂质体封装的氯膦酸盐处理的影响 最多一年的颈椎和胸科科学模型。具体来说，该赠款试图：目标1：评估 急性MD对骨髓骨气，生物分布和毒性的剂量反应影响；目标2：确定 急性MD对慢性科学大鼠的运动，感觉和自主功能的恢复的功效。目标3： 确定急性MD对宫颈科学后呼吸运动和前肢功能的恢复的影响。 检查宫颈和胸科SCI后MD的影响的组合方法将提供 关于单核细胞功能对感觉，自主神经，疼痛和 呼吸结果。克罗德膦酸盐（aka二氯甲基二膦酸盐）处理的可行性 据报道，在SCI中，大约40年前，我们的建议很重要，因为我们的数据是我们的数据 研究可以适应治疗人类科学，并有望对翻译产生至关重要的影响。