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(r-mtbi)可导致多年的神经损伤。 在损伤停止后，会增加晚年患神经退行性疾病的风险。至 到目前为止，还没有开发出合适的治疗策略来拯救持续的和长期的阴性 R-mTBI的后果。因此，应该更多地强调理解潜在的 驱动r-mTBI后长期神经功能障碍的病理生物学机制，因为这可能导致 确定新的治疗靶点。神经炎是人类和临床前疾病的共同特征。 脑外伤动物模型的建立。影响神经炎性反应传播和持续的因素 在脑外伤的慢性后遗症中，仍然难以捉摸。我们已经建立了一种重复性脑损伤的小鼠模型。 人类脑损伤的许多特征，因此代表了这样一个翻译相关的临床前平台 学习。从这个模型中，我们已经生成了一个小胶质细胞基因图谱的分子文库 损伤后的时间点，提供了小胶质细胞神经炎的独特和详细的时间过程 对r-mTBI的反应。特别是，我们观察到了能量、生物能量学、血糖和血脂的缺陷。 新陈代谢，以及慢性时间点的促炎信号，这似乎是由损失驱动的 小胶质细胞中组成性PPAR𝛾𝛾信号的表达。PPAR𝛾𝛾在多种细胞类型中表达，在多种细胞中发挥重要作用 在调节糖脂代谢、能量生物能量学和炎症方面。使用PPAR𝛾𝛾进行治疗 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有效性。 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信号转导所需的特异性。在这个新的应用程序中，我们计划 阐明PPARγ在脑挫伤和脑损伤后调节脑小胶质细胞反应中的构成作用 证明小胶质细胞特异性PPARγ激活是否减轻脑损伤介导的神经炎症和 在我们的r-mTBI模型中，随后出现了神经变性。我们将比较脑损伤依赖的反应在 存在或不存在PPARγ激活以揭示与有利的 R-mTBI后的结果和代表新的治疗靶点。我们将通过使用三苯氧胺来实现这一点 可诱导的小鼠模型，特异性靶向小胶质细胞中PPARγ的激活。我们将诱导PPARγ激活 在小胶质细胞中使用损伤前的三苯氧胺治疗范例，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图谱。我们的目标是澄清 在r-mTBI的慢性后遗症中，PPARγ作为小胶质细胞病理生物学的主要调节因子 鉴定由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点进行探索，不仅在脑损伤中，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.