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诱发神经损伤， 增加ADRD的风险。尚未开发出改善疾病的治疗策略来缓解长期的 r-mTBI的后果迫切需要推进我们目前对细胞机制的理解， 继发性损伤事件的级联，因为这可能导致新疗法的鉴定和开发。 星形胶质细胞在这些继发性损伤事件中起重要作用。在急性损伤后，它们经历了一个戏剧性的转录组学变化， 和形态学上的转变。反应性星形胶质细胞可以被极化成不同的状态， 神经毒性会影响大脑恢复神经保护性星形胶质细胞可以用来创建物理屏障， 限制损伤的扩散，防止兴奋毒性，促进神经元的代谢支持，并释放营养因子， 神经修复而神经毒性星形胶质细胞可以发挥神经炎症和胶质瘢痕形成的双重作用， 轴突再生和促进神经元损伤，这可能伴随着失去其组成性支持， 角色我们对调节健康脑或脑梗死后星形胶质细胞表型和反应的机制的了解， 伤害是缺乏的。为了解决这一问题，我们建立了一个小鼠模型的r-mTBI，重现了许多特点，人类 TBI，因此代表了预防相关的临床前平台。使用这个模型，我们产生了一个分子库， 损伤后一系列时间点的星形胶质细胞基因谱，提供了星形胶质细胞独特且详细的时间进程 对TBI的回应特别是，我们揭示了细胞代谢，氧化应激和促炎信号的缺陷， 星形胶质细胞，这似乎是由组成性过氧化物酶体增殖物激活受体的损失的影响？星形胶质细胞中的信号。过氧化物酶体增殖物激活受体γ高表达 在神经胶质细胞中，并在调节细胞代谢、生物能量学、细胞存活和免疫功能中发挥重要的组成性作用。 用PPARγ激动剂治疗已经显示出在恢复行为结果和挽救星形胶质细胞病理生物学方面的功效， r-mTBI模型由于多种细胞类型表达PPARγ受体，因此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。在这个建议中，我们计划阐明PPARγ在调节细胞凋亡中的组成性作用。 星形胶质细胞反应在健康的大脑和TBI的背景下，并证明是否星形胶质细胞特异性的过氧化物酶体增殖物激活受体γ 活化减轻了TBI介导的星形胶质细胞活化、炎症、神经变性和功能结果。我们将 通过利用特异性靶向星形胶质细胞中的PPARγ活化的他莫昔芬诱导型小鼠模型来实现这一点。我们将 使用三个治疗时间窗（即，伤前、早期和延迟），并检查 损伤后6个月星形胶质细胞的功能和病理生物学结果、scRNAseq谱和功能活性。在我们 scRNAseq研究中，我们将比较存在或不存在PPARγ活化的TBI依赖性反应，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，并代表新的 治疗和翻译目标。我们的目标是阐明PPARγ作为星形胶质细胞病理生物学调节因子的作用， TBI的慢性后遗症，并确定星形胶质细胞中的修复机制，从而推动有利的结果， 新的星形胶质细胞特异性靶点在未来的工作中，不仅在TBI，但ADRD星形胶质细胞病理生物学是一个关键的贡献者。