The role of PPARγ in astrocyte pathobiology after exposure to repetitive mild traumatic brain injury

PPARγ 在重复性轻度脑外伤后星形胶质细胞病理学中的作用

• 批准号: 10739968
• 负责人: Joseph O Ojo
• 金额: $ 44.94万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739968
• 关键词: Acute; Address; Adopted; Agonist; Alzheimer' s disease related dementia; Astrocytes; Automobile Driving; Autopsy; Behavioral; Biochemical Markers; Bioenergetics; Blood - brain barrier anatomy; Brain; Brain Injuries; Calcium; Cell Survival; Cells; Cellular Metabolic Process; Cerebrovascular Circulation; Chronic; Cicatrix; Clinical; Clinical Trials; Color; Consultations; Contracts; Data; Development; Disease; Ensure; Event; Exposure to; Flow Cytometry; Future; Gene Expression; Genes; Genetic; Gliosis; Goals; Human; Image; Impairment; Inflammation; Inflammatory; Injury; Intervention; Investigation; Knowledge; Learning; Ligands; Lipid A; Mediating; Memory; Metabolic; Metabolism; Microglia; Modeling; Molecular Bank; Morphology; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurons; Outcome; Oxidative Stress; PPAR gamma; Pathogenesis; Pathologic; Pathology; Performance; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Phenotype; Play; Pre-Clinical Model; Property; Receptor Activation; Recovery; Research Design; Retrospective Studies; Risk; Role; Sensorimotor functions; Signal Transduction; Sorting; Specificity; Suspensions; Synapses; TBI Patients; Tamoxifen; Therapeutic; Time; Tissues; United States National Institutes of Health; Work; astrogliosis; axon injury; axon regeneration; behavioral outcome; cell type; constitutive expression; density; differential expression; functional outcomes; immune function; immunoregulation; in vivo; lipid metabolism; mild traumatic brain injury; mouse model; neurobehavioral; neuroinflammation; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutics; overexpression; pharmacologic; pre-clinical; prophylactic; receptor; response; single cell analysis; tau Proteins; therapeutic target; timeline; transcriptome sequencing; transcriptomics; translational potential; treatment strategy

Repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years after the cessation of injury, increasing the risk for ADRD. No disease-modifying treatment strategies have been developed to mitigate the long-term consequences of r-mTBI. There is an urgent need to advance our current understanding of the cellular mechanisms driving the cascade of secondary injury events, as this could lead to the identification and development of novel therapeutics. Astrocytes play an important role in these secondary injury events. After acute insult, they undergo a dramatic transcriptomic and morphological transformation. Reactive astrocytes can be polarized into different states adopting neuroprotective or neurotoxic properties that can influence brain recovery. Neuroprotective astrocytes can serve to create a physical barrier to limit the spread of damage, preventexcitotoxicity, boost metabolic support for neurons, and release trophic factors to promote neurorepair. While neurotoxic astrocytes can take a dual role of neuroinflammation and glial scar formation that inhibits axonal regeneration and promotes neuronal damage, and this can be accompanied by loss of their constitutive supportive roles. Our knowledge of the mechanisms that regulate astrocyte phenotypes and responses in the healthy brain or after brain injury is lacking. To address this, we established a mouse model of r-mTBI that recapitulates many of the features of human TBI and thus represents a translationally relevant preclinical platform. Using this model, we generated a molecular library of astroglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the astroglia response to TBI. Particularly, we reveal deficits in cellular metabolism, oxidative stress and a proinflammatory signature of astroglia, which appears to be influenced by the loss of constitutive PPAR? signaling in astrocytes. PPARγ is highly expressed in glial cells and plays a vital constitutive role in regulating cell metabolism, bioenergetics, cell survival and immune function. Treatment with a PPARγ agonist has shown efficacy in restoring behavioral outcomes and rescuing astroglia pathobiology in our r-mTBI model. Because multiple cell types express PPARγ receptors, PPARγ ligands lack the specificity needed to target astroglia specific PPARγ signaling in vivo. In this proposal, we plan to clarify the constitutive role of PPARγ in regulating astroglial responses in the healthy brain and in the context of TBI, and demonstrate whether astroglia specific PPARγ activation mitigates TBI mediated astroglia activation, inflammation, neurodegeneration and functional outcomes. We will achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in astrocytes. We will induce PPARγ activation inastrocytes using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine functional and pathobiological outcomes, scRNAseq profiles and functional activities of astroglia at 6 mo post-injury. In our scRNAseq study, we will compare TBI-dependent responses in the presence or absence of PPARγ activation to reveal astroglia-specific targets that correlate with favorable outcomes at the optimaltime-window of treatment, and represent novel therapeutic and translational targets. Our goal is to clarify the role of PPARγ as a regulator of astroglia pathobiology in the chronic sequelae of TBI and identify reparative mechanisms in astrocytes driving favorable outcomes that can be explored as novel astrocyte specific targets in future work, not only in TBI but ADRD where astrocyte pathobiology is a critical contributor.

重复性轻度创伤性脑损伤(r-mTBI)可在损伤停止多年后导致神经损伤， 增加了ADRD的风险。目前还没有制定出治疗疾病的策略来缓解长期的 R-mTBI的后果。迫切需要推进我们目前对细胞驱动机制的理解 继发性伤害事件的级联，因为这可能导致新的治疗方法的确定和发展。 星形胶质细胞在这些继发性损伤事件中起着重要作用。在受到严重侮辱后，他们经历了戏剧性的转录 和形态变化。反应性星形胶质细胞可极化为不同状态采用神经保护或 可能影响大脑恢复的神经毒性特性。神经保护性星形胶质细胞可以产生一种物理屏障 限制损伤的扩散，预防兴奋毒性，增强对神经元的代谢支持，并释放营养因子以促进 神经修复。而神经毒性星形胶质细胞可以发挥神经炎症和神经胶质瘢痕形成的双重作用，从而抑制 轴突再生并促进神经元损伤，这可能伴随着其结构性支持的丧失 角色。我们对健康大脑或脑后星形胶质细胞表型和反应调节机制的认识 伤病是缺乏的。为了解决这一问题，我们建立了一个r-mTBI小鼠模型，该模型概括了人类的许多特征。 因此，它代表了一个翻译上相关的临床前平台。使用这个模型，我们生成了一个分子文库 星形胶质细胞基因图谱，在损伤后的一系列时间点，提供了星形胶质细胞独特而详细的时间进程 对TBI的反应。特别是，我们揭示了细胞代谢的缺陷，氧化应激和促炎标志 星形胶质细胞，它似乎受到结构性PPAR缺失的影响？星形胶质细胞中的信号。PPARγ高表达 在调节细胞代谢、生物能量学、细胞存活和免疫功能方面起着重要的结构性作用。 用PPARγ激动剂治疗在恢复行为结果和挽救星形胶质细胞病理生物学方面显示出有效 我们的r-mTBI模型。由于多种细胞类型表达PPARγ受体，PPARγ配体缺乏靶向所需的特异性 星形胶质细胞特异性PPARγ信号转导体内。在这项建议中，我们计划澄清pparγ在调节 星形胶质细胞在健康大脑和脑外伤背景下的反应，并证明星形胶质细胞特异性PPARγ 激活可减轻脑损伤介导的星形胶质细胞激活、炎症、神经退行性变和功能结果。我们会 通过利用三苯氧胺诱导的小鼠模型来实现这一点，该模型专门针对星形胶质细胞中的PPARγ激活。我们会 用三个治疗时间窗(即损伤前、早期和延迟)诱导星形胶质细胞PPARγ激活，并检测 损伤后6个月的功能和病理生物学结果、星形胶质细胞的scRNAseq谱和功能活性。在我们的 ScRNAseq研究，我们将比较存在或不存在PPARγ激活的脑损伤依赖反应，以揭示 星形胶质细胞特异性靶点与最佳治疗时间窗的有利结果相关，并代表了新的 治疗和转化靶点。我们的目标是阐明PPARγ在星形胶质细胞病理生物学中的调节作用。 脑外伤的慢性后遗症和确定星形胶质细胞的修复机制推动良好的结果，可以探索如下 新的星形胶质细胞特异性靶点在未来的工作中，不仅在TBI，而且在ADRD中，星形胶质细胞的病理生物学是一个关键因素。