The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury

重复性轻度创伤性脑损伤后 PPARγ 在小胶质细胞病理学中的作用

基本信息

批准号：
10557217
负责人：
Joseph O Ojo
金额：
$ 16.34万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557217
关键词：
Address Agonist Alzheimer&apos s disease related dementia Animal Model Astrocytes Automobile Driving Behavioral Biochemical Markers Bioenergetics Blood - brain barrier anatomy Brain Chronic Clinical Clinical Trials Consultations Cre-LoxP Data Development Elderly Ensure Event Exposure to Future Genes Gliosis Goals Health Human Inflammation Inflammatory Inflammatory Response Injury Investigation Learning Ligands Link Mediating Memory Microglia Modeling Molecular Bank Nerve Degeneration Nervous System Trauma Neurodegenerative Disorders Neuroglia Neurologic Neurologic Deficit Neurologic Dysfunctions Neurons Outcome PPAR gamma Pathogenesis Pathology Patients Performance Phenotype Play Pre-Clinical Model Receptor Activation Research Design Retrospective Studies Risk Role Sensorimotor functions Signal Transduction Specificity Synapses TBI Patients Tamoxifen Therapeutic Time Traumatic Brain Injury Work astrogliosis axon injury cell type functional outcomes genetic signature glucose metabolism immunoregulation in vivo inducible Cre lipid metabolism mild traumatic brain injury mouse model neurobehavioral neuroinflammation neuropathology neuroprotection new therapeutic target novel overexpression pharmacologic pre-clinical receptor response tau Proteins therapeutic target timeline transcriptome transcriptome sequencing transcriptomics translational potential treatment strategy

项目摘要

Exposure to repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years following the cessation of injury, contributing to an increased risk for neurodegenerative disease in later life. To date, no suitable treatment strategies have been developed to rescue the persistent and long-term negative consequences of r-mTBI. A greater emphasis should therefore be placed on understanding the underlying pathobiological mechanisms driving the long-term neurological deficits after r-mTBI, as this could lead to the identification of novel therapeutic targets. Neuroinflammation is a common feature of human and preclinical animal models of TBI. The factors governing the propagation and persistence of neuroinflammatory responses in the chronic sequelae of TBI remain elusive. We have established a mouse model of r-mTBI that recapitulates many of the features of human TBI and thus represents a translationally relevant preclinical platform for such studies. From this model we have generated a molecular library of microglia gene profiles at a range of timepoints post-injury that provides a unique and detailed time-course of the microglial neuroinflammatory response to r-mTBI. Particularly, we observed deficits in energy bioenergetics, altered glucose and lipid metabolism, and a pro-inflammatory signature at chronic timepoints, which appeared to be driven by the loss of constitutive PPAR𝛾𝛾 signaling in microglia. PPAR𝛾𝛾 is expressed in multiple cell types and plays a critical role in regulating glucose and lipid metabolism, energy bioenergetics and inflammation. Treatment with a PPAR𝛾𝛾 agonist has shown efficacy in restoring behavioral and microglial pathobiological consequences in our r- mTBI model. However, because multiple cell types express PPARγ receptors, pharmacological PPARγ ligands lack the specificity needed to target microglial PPARγ signaling in vivo. In this new application, we plan to clarify the constitutive role of PPARγ in regulating brain microglial cell responses in the context of TBI and demonstrate whether microglia specific PPARγ activation mitigates TBI mediated neuroinflammation and subsequent neurodegeneration in our r-mTBI model. We will compare TBI-dependent responses in the presence or absence of PPARγ activation to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in microglia. We will induce PPARγ activation in microglia using a pre-injury tamoxifen treatment paradigm, and examine functional and pathobiological outcomes, and glial cell transcriptomic profiles at 3 and 6 mo post-injury. Our goal is to clarify the role of PPARγ as a master regulator of microglial pathobiology in the chronic sequelae of r-mTBI, and to identify unique gene signatures and reparative mechanisms in microglia induced by PPAR𝛾𝛾 activation that can be explored as novel microglial specific targets, not only in TBI but other neurodegenerative diseases where neuroinflammation is a critical contributor.

接触重复的轻度外伤性脑损伤（R-MTBI）可能会诱导神经系统损害多年停止伤害之后，在后来的生活中导致神经退行性疾病的风险增加。到日期，尚未制定合适的治疗策略来挽救持久和长期负面的策略 R-MTBI的后果。因此，应该更加重视理解基础病理生物学机制驱动R-MTBI之后的长期神经系统防御，因为这可能导致鉴定新的治疗靶标。神经炎症是人类和临床前的共同特征 TBI的动物模型。负责神经炎症反应的传播和持久性的因素在慢性后遗症中，TBI仍然难以捉摸。我们已经建立了R-MTBI的鼠标模型，该模型概括了人类TBI的许多特征，因此代表了一个翻译相关的临床前平台研究。从该模型中，我们在一系列范围内生成了一个小胶质细胞基因曲线的分子库时间点后的损伤后，提供了小胶质神经炎症的独特而详细的时间课程对R-MTBI的响应。特别是，我们观察到定义在能量生物能，葡萄糖和脂质的改变代谢，以及在慢性时点的促炎性签名，这似乎是由损失驱动的小胶质细胞中的本构PPAR𝛾𝛾信号传导。 PPAR𝛾𝛾在多种细胞类型中表达，并且起着至关重要的作用在控制葡萄糖和脂质代谢，能量生物能和注射时。用PPAR𝛾𝛾治疗激动剂在我们的r-中显示了恢复行为和小胶质细胞生物学后果的效率 MTBI模型。但是，由于多种细胞类型表达PPARγ受体，因此药物PPARγ配体缺乏靶向小胶质细胞PPARγ信号传导所需的特异性。在这个新应用程序中，我们计划阐明在TBI和证明小胶质细胞特异性PPARγ活化是否减轻TBI介导的神经炎症和我们的R-MTBI模型中的随后神经变性。我们将比较依赖TBI的响应存在或不存在PPARγ激活，以揭示与有利相关的小胶质细胞特定靶标 R-MTBI之后的结果并代表新的治疗靶标。我们将使用他莫昔芬实现这一目标可诱导小鼠模型，该模型专门针对小胶质细胞中的PPARγ激活。我们将诱导PPARγ激活在小胶质细胞中使用损伤前的罗昔佛治疗范式，并检查功能和病理学结局和损伤后3和6 mo的胶质细胞转录组谱。我们的目标是阐明 PPARγ是R-MTBI慢性后遗症小胶质细胞生物学的主要调节剂，鉴定由PPAR激活引起的小胶质细胞中的独特基因特征和修复机制，可以作为新的小胶质细胞特定靶标的探索，不仅在TBI，而且在其他神经退行性疾病中神经炎症是关键的贡献者。