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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

损伤停止后，重复性轻度脑损伤（R-MTBI）可诱导神经系统损害，增加ADRD的风险。尚未制定改善疾病的治疗策略来减轻长期的缓解 R-MTBI的后果。迫切需要提高我们当前对驱动细胞机制的理解一系列继发性伤害事件，因为这可能会导致新疗法的识别和发展。星形胶质细胞在这些继发性伤害事件中起着重要作用。急性受伤后，他们发生了戏剧性的转录组和形态转化。反应性星形胶质细胞可以两极化到采用神经保护或的不同状态可以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为限制损害的传播，预防毒性毒性，增强对神经元的代谢支持，并释放营养因素以促进神经台。虽然神经毒性星形胶质细胞可以双重作用神经炎症和神经胶质疤痕形成，从而抑制轴突再生并促进神经元损伤，这可以通过失去其本构支持来实现角色。我们对健康大脑中星形胶质细胞表型和反应的机制的了解缺乏伤害。为了解决这个问题，我们建立了R-MTBI的鼠标模型，该模型概括了人类的许多特征 TBI，因此代表了一个翻译相关的临床前平台。使用此模型，我们生成了一个分子库星形胶质体基因剖面，在伤害后的一系列时间点，提供了独特而详细的星形胶质细胞。对TBI的反应。特别是，我们揭示了细胞代谢，氧化应激和促炎的特征的防御 Astroglia，似乎受构型PPAR丢失的影响？星形胶质细胞中的信号传导。 PPARγ高度表达在神经胶质细胞中，在调节细胞代谢，生物能，细胞存活和免疫学功能中起着至关重要的作用。用PPARγ激动剂治疗在恢复行为结局和挽救星形胶质病病理学方面的效率我们的R-MTBI模型。由于多种细胞类型表达PPARγ受体，因此PPARγ配体缺乏靶向靶标所需的特异性星体特异性PPARγ信号传导体内。在此提案中，我们计划阐明PPARγ在调节中的构成作用在健康的大脑和TBI的背景下，星形胶质细胞反应激活减轻TBI介导的星形胶质激活，感染，神经退行性和功能结果。我们将通过使用他莫昔芬诱导小鼠模型来实现这一目标，该模型专门针对星形胶质细胞中的PPARγ激活。我们将使用三种治疗时间旋转（即，遭受前，早期和延迟）诱导PPARγ激活界细胞，并检查后6月6日，Astroglia的功能和病理学结果，SCRNASEQ谱和功能活动。在我们的 SCRNASEQ研究，我们将在存在或不存在PPARγ激活的情况下比较TBI依赖性响应以揭示在最佳时期窗口上与有利的结果相关的星形胶质细胞特异性目标，并代表新颖治疗和翻译靶标。我们的目标是阐明PPARγ作为星形胶质细胞生物学的调节剂在 TBI的慢性后遗症，并确定星形胶质细胞中的修复机制，以促进有利的结果，可以探索为新型的星形胶质细胞在未来工作中的特定目标，不仅在TBI中，而且在ADRD中，星形胶质细胞病理学是关键的贡献者。