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）可导致神经系统损伤多年 在损伤停止后，导致晚年神经退行性疾病的风险增加。到 迄今为止，尚未开发出合适的治疗策略来挽救持续和长期阴性 r-mTBI的后果因此，应更加重视了解 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 新的治疗靶点的鉴定。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 创伤性脑损伤的慢性后遗症仍然难以捉摸。我们已经建立了r-mTBI的小鼠模型， 因此，它代表了用于此类TBI的预防相关的临床前平台。 问题研究从这个模型中，我们已经产生了一个小胶质细胞基因谱的分子文库， 损伤后的时间点，提供了一个独特的和详细的时间过程的小胶质细胞神经炎症 对r-mTBI的反应。特别是，我们观察到能量生物能学的缺陷，改变葡萄糖和脂质 代谢，以及慢性时间点的促炎特征，这似乎是由损失驱动的。 小胶质细胞中的组成型PPAR γ信号传导。𝛾𝛾过氧化物酶体增殖物激活受体在多种细胞类型中表达，𝛾𝛾 在调节葡萄糖和脂质代谢、能量生物能学和炎症中。治疗与PPAR拮抗剂𝛾𝛾 在我们的研究中，激动剂在恢复行为和小胶质细胞病理生物学后果方面显示出功效， mTBI模型。然而，由于多种细胞类型表达PPAR γ受体，药理学上的PPAR γ配体， 缺乏体内靶向小胶质细胞PPAR γ信号传导所需的特异性。在这个新的应用程序中，我们计划 阐明在TBI背景下，PPAR γ在调节脑小胶质细胞反应中的组成性作用， 证明小胶质细胞特异性PPAR γ活化是否减轻TBI介导的神经炎症， 在我们的r-mTBI模型中随后的神经变性。我们将比较TBI依赖的反应， 存在或不存在PPAR γ活化，以揭示与有利的 r-mTBI后的结果，代表了新的治疗靶点。我们将通过使用他莫昔芬 可诱导小鼠模型，特异性靶向小胶质细胞中的PPAR γ活化。我们将诱导过氧化物酶体增殖物激活受体γ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 结果和损伤后3和6个月的胶质细胞转录组学特征。我们的目标是澄清 PPAR γ作为r-mTBI慢性后遗症中小胶质细胞病理生物学的主要调节因子，以及 为了鉴定由PPAR γ激活诱导的小胶质细胞中独特的基因特征和修复机制，𝛾𝛾 可以作为新的小胶质细胞特异性靶点，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.