Role of senescent cells in pathogenesis of contusive spinal cord injury

衰老细胞在挫伤性脊髓损伤发病机制中的作用

基本信息

批准号：
10116681
负责人：
MICHAL HETMAN
金额：
$ 42.92万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116681
关键词：
Acute Address Aging Amyloidosis Anatomy Anxiety Apoptosis Arthritis Astrocytes Atherosclerosis Biological Assay Blood Vessels Cell Aging Cell Cycle Cells Chronic Cicatrix Clinical Clinical Trials Contusions Cyclin-Dependent Kinase Inhibitor 2A DNA Damage Dasatinib Data Diabetes Mellitus Disease Drug Combinations Elements Endothelial Cells Environment Fibroblasts Frontotemporal Dementia Functional disorder Ganciclovir Gliosis HSV-Tk Gene Herpes Simplex Infections Hindlimb Human Inflammation Mediators Inflammatory Response Injury Locomotion Locomotor Recovery Luciferases Mechanics Mediator of activation protein Microglia Modeling Monitor Mus Natural regeneration Nerve Degeneration Neuroglia Neuronal Plasticity Neurons Obesity Oligodendroglia Outcome Pathogenesis Pathogenicity Pathology Pericytes Permeability Pharmaceutical Preparations Pharmacogenetics Pharmacology Phase Phenotype Proliferating Quercetin Recovery Recovery of Function Renilla Luciferases Reporter Genes Reporting Rodent Role Sorting - Cell Movement Spinal Cord Spinal Cord Contusions Spinal cord injury Synaptic plasticity Testing Therapeutic Thoracic spinal cord structure Thymidine Kinase Tissues Transgenic Organisms Trauma Vascular Diseases Wild Type Mouse age related cell type central nervous system injury cytotoxic effective therapy improved improved outcome in situ imaging mouse model neuroinflammation new therapeutic target novel oligodendrocyte precursor oncoprotein p21 precursor cell promoter red fluorescent protein response senescence spatiotemporal white matter white matter damage

项目摘要

After spinal cord injury (SCI), initial mechanical damage is followed by a secondary injury that exacerbates tissue destruction and functional deficits. In contusive thoracic SCI, white matter damage, which progresses for weeks post-injury, is the critical anatomical determinant of locomotor dysfunction. Few targets have been identified whose manipulation reduces SCI-associated secondary injury with a therapeutic window of <12-24 h. Although locomotor recovery is observed in SCI rodents, it is usually incomplete. The limits to recovery involve neuron and oligodendrocyte loss, prolonged inflammatory responses, vascular dysfunction, lack of efficient regeneration, and/or a finite capacity of synaptic plasticity. Breaking the ceiling of locomotor recovery in rodents remains a major challenge. Proliferating cells that accumulate DNA damage may undergo cellular senescence. Senescence-associated induction of the cyclin-dependent kinases (CDK) inhibitors p21 and p16 triggers permanent exit from the cell cycle. The senescence-associated secretory phenotype (SASP) involves secretion of multiple cytotoxic pro-inflammatory mediators. Elimination of senescent cells (senolysis) improves many age-dependent pathologies and reduces neurodegeneration in mouse models of fronto-temporal dementia or β-amyloidosis. In those cases, improved outcomes were associated with elimination of senescent microglia/astrocytes or oligodendrocyte precursor cells (OPCs). As those glial cells proliferate in response to CNS injury, their senescence is a likely by-product of trauma-induced gliosis. Our preliminary data reveal increased expression of cellular senescence markers at dpi 3 and 42 following T9 contusive SCI. Hence, by promoting neuroinflammation and tissue scarring, senescent cells may increase white matter loss and compromise neurorepair/neuroplasticity after contusive SCI. We hypothesize that accumulation of senescent cells after SCI contributes to progressive white matter loss and reduces recovery of locomotor function. In aim 1 we will determine the identity and spatio-temporal distribution of senescent cells in the spinal cord of SCI mice. In aim 2 we will test effects of pharmacological (2a) or pharmacogenetic (2b) senolysis on white matter sparing and hindlimb locomotor function after moderate T9 contusive SCI. Effects of senolysis will be evaluated by analyzing senescence markers, neuroinflammation, reactive gliosis, apoptosis, white matter sparing, and hindlimb locomotion. These studies will conclusively evaluate the pathogenic significance of SCI- associated cellular senescence. As senolytic drugs are already in use in clinical trials for other diseases, these studies may define a novel and readily translatable therapeutic treatment for both acute and chronic SCI- induced pathologies. Although it has been proposed that organismal aging may modify outcome of SCI, this application is focused on an entirely distinct issue that has not been previously addressed: the pathogenic role of injury-induced cellular senescence.

脊髓损伤（SCI）后，初始机械损伤之后是加重的继发性损伤组织破坏和功能不足。在续胸科SCI中，白质损坏，进展伤害后几周是运动功能障碍的关键解剖学决定剂。很少有目标被鉴定出其操纵可通过<12-24 h的治疗窗口减少SCI相关的继发损伤。尽管在SCI啮齿动物中观察到运动恢复，但通常是不完整的。恢复的限制涉及神经元和少突胶质细胞丧失，长时间炎症反应，血管功能障碍，缺乏有效再生和/或突触可塑性的有限容量。破坏运动恢复的天花板啮齿动物仍然是一个重大挑战。累积DNA损伤的增殖细胞可能会经历细胞衰老。细胞周期蛋白依赖性激酶（CDK）抑制剂p21和p16的衰老相关诱导触发了从细胞周期的永久退出。感应相关的秘书表型（SASP）涉及多种细胞毒性促炎性介质的分泌。消除感觉细胞（Senolsesy）改善许多年龄依赖性病理并降低了额叶的小鼠模型中的神经退行性痴呆或β-淀粉样变性。在这种情况下，改善的结果与消除感觉有关小胶质细胞或少突胶质细胞前体细胞（OPC）。因为这些神经胶质细胞响应于中枢神经系统损伤，它们的感受是创伤引起的神经胶质病的副产品。我们的初步数据显示在T9 Copusty Sci之后，DPI 3和42处细胞感应标记的表达增加。因此，由促进神经炎症和组织疤痕，感觉细胞可能会增加白质的丧失和欺骗性的SCI后神经保留/神经可塑性妥协。我们假设感觉的积累 SCI后的细胞有助于进行性白质损失并减少运动功能的恢复。目标 1我们将确定SCI脊髓中感觉细胞的身份和时空分布老鼠。在AIM 2中，我们将测试药理学（2a）或药物遗传学（2B）鼻溶液对白质的影响中度T9抑制性SCI后，支撑和后肢的运动功能。鼻溶液的影响将是通过分析感应标记，神经炎症，反应性神经胶质病，凋亡，白质评估保留和后肢的运动。这些研究将最终评估Sci-I的致病意义相关的细胞感应。由于其他疾病的临床试验中已经使用了鼻溶剂，因此研究可能为急性和慢性Sci-定义一种新颖且容易翻译的治疗方法诱导的病理。尽管已经提出有机衰老可能会改变SCI的结果，但应用集中于以前尚未解决的完全不同的问题：致病作用损伤诱导的细胞感应。