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

暴露于重复性轻度创伤性脑损伤 (r-mTBI) 可导致多年的神经损伤 损伤停止后，会增加晚年患神经退行性疾病的风险。至 迄今为止，尚未开发出合适的治疗策略来挽救持续且长期的负面影响 r-mTBI 的后果。因此，应更加重视对底层的理解 r-mTBI 后驱动长期神经功能缺损的病理生物学机制，因为这可能导致 识别新的治疗靶点。神经炎症是人类和临床前的共同特征 TBI 动物模型。控制神经炎症反应传播和持续的因素 TBI 的慢性后遗症仍然难以捉摸。我们建立了 r-mTBI 小鼠模型，该模型概括了 人类 TBI 的许多特征，因此代表了此类药物的翻译相关的临床前平台 研究。从这个模型中，我们生成了一系列小胶质细胞基因谱的分子库 损伤后时间点，提供小胶质细胞神经炎症的独特且详细的时间过程 对 r-mTBI 的反应。特别是，我们观察到能量生物能学的缺陷、葡萄糖和脂质的改变 新陈代谢和慢性时间点的促炎特征，这似乎是由损失驱动的 小胶质细胞中组成型 PPAR𝛾𝛾 信号传导的研究。 PPAR𝛾𝛾在多种细胞类型中表达并发挥关键作用 调节葡萄糖和脂质代谢、能量生物能学和炎症。 PPAR𝛾𝛾治疗 激动剂已显示出在恢复我们的 r-行为和小胶质细胞病理生物学后果方面的功效 mTBI 模型。然而，由于多种细胞类型表达 PPARγ 受体，药理学 PPARγ 配体 缺乏体内靶向小胶质细胞 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 PPARγ 在 TBI 背景下调节脑小胶质细胞反应的组成作用 证明小胶质细胞特异性 PPARγ 激活是否可以减轻 TBI 介导的神经炎症 r-mTBI 模型中随后出现神经退行性变。我们将比较 TBI 依赖性反应 PPARγ 激活的存在或不存在可揭示与有利相关的小胶质细胞特异性靶点 r-mTBI 后的结果并代表新的治疗靶点。我们将通过使用他莫昔芬来实现这一目标 专门针对小胶质细胞中 PPARγ 激活的诱导小鼠模型。我们将诱导 PPARγ 激活 在小胶质细胞中使用损伤前他莫昔芬治疗范例，并检查功能和病理生物学 结果以及损伤后 3 个月和 6 个月的神经胶质细胞转录组谱。我们的目标是阐明 PPARγ 作为 r-mTBI 慢性后遗症中小胶质细胞病理学的主要调节因子，以及 识别 PPAR𝛾𝛾 激活诱导的小胶质细胞中独特的基因特征和修复机制 可以作为新的小胶质细胞特异性靶标进行探索，不仅在 TBI 中，而且在其他神经退行性疾病中 神经炎症是一个关键因素。

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.