Mechanisms and Therapeutic Targeting of Chronic Neuroinflammation in Traumatic Brain Injury

创伤性脑损伤（TBI）是美国死亡和残疾的主要原因之一。 研究表明，TBI后存在慢性神经炎症，这有助于进行性神经损伤。 神经变性、白色物质损失和认知能力下降。不幸的是，病理过程 对潜在的慢性神经炎症知之甚少。本研究的总体目标是 阐明TBI后慢性神经炎症的机制， 针对这些机制的干预措施。我们的核心假设是， 促炎性和神经毒性A1星形胶质细胞在慢性神经炎症、进行性神经炎和神经毒性中起关键作用。 神经变性和TBI后长期认知下降。A1星形胶质细胞是一种失去 能够执行其正常功能，产生补充成分，不太能够促进 形成新的突触，并释放可损伤或杀死神经元和少突胶质细胞的因子[9]。 此外，我们的初步数据表明，A1星形胶质细胞表达“衰老”标记， 衰老，提高了衰老药物可用于消融A1星形胶质细胞的可能性， TBI治疗提出以下具体目标来检验我们的假设。目标1的特点是 A1星形胶质细胞在TBI中的诱导、机制和作用。这将通过以下方式实现：1A。 表征TBI后脑中A1/A2星形胶质细胞诱导和星形胶质细胞转录组变化。1b. 确定小胶质细胞在TBI后脑中A1星形胶质细胞诱导中的作用。1c.确定神经毒性 TBI后从脑中分离的A1星形胶质细胞的能力。1d.确定A1星形胶质细胞是否具有 在TBI后的长期神经病理学和功能结果中起关键作用。目标2将决定 靶向衰老A1星形胶质细胞和小胶质细胞作为TBI的潜在疗法的治疗功效。这 将通过以下方式实现：2a.确定衰老清除药物消除衰老A1的治疗效果 星形胶质细胞和衰老的小胶质细胞，并减少TBI后长期的神经病理学和功能缺陷。 2b.建立TBI中衰老药物治疗的治疗窗口。2c.确定持续时间 老年痴呆药物对创伤性脑损伤的有益作用。该研究在概念上具有高度创新性， 提出了最近鉴定的A1星形胶质细胞和衰老细胞在TBI病理和慢性炎症中的关键作用。 神经炎症它也是高度创新的技术，在提出使用一种新的三重敲除 三种A1诱导因子的小鼠模型，用于神经胶质细胞转录组谱分析的RNA-seq，以及 建议使用最近确定的senolytics作为潜在的治疗，以改善TBI的长期结果。如果 如果成功，这些研究将对该领域产生重大影响，因为它们可以提供一种治疗方法的希望， 可以在TBI后几个月甚至几年使用，现在除了支持性治疗外没有其他治疗选择。 在乎

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the United States. Research has shown that there is chronic neuroinflammation following TBI, which contributes to progressive neurodegeneration, white matter loss and cognitive decline. Unfortunately, the pathological processes underlying chronic neuroinflammation are poorly understood. The overall objective of the current study is to elucidate the mechanisms that underlie chronic neuroinflammation after TBI and test therapeutic interventions that target these mechanisms. Our central hypothesis is that newly discovered proinflammatory and neurotoxic A1 astrocytes play a key role in chronic neuroinflammation, progressive neurodegeneration, and cognitive decline long-term after TBI. A1 astrocytes are astrocytes that lose the ability to carry out their normal functions, produce complement components, are less able to promote the formation of new synapses, and release factors which can damage or kill neurons and oligodendrocytes [9]. Furthermore, our preliminary data indicates that A1 astrocytes express “senescent” markers and are senescent, raising the possibility that senolytic drugs could be used to ablate A1 astrocytes as a potential therapy in TBI. The following specific aims are proposed to test our hypothesis. Aim 1 would characterize the induction, underlying mechanisms and role of A1 astrocytes in TBI. This would be achieved by: 1a. Characterizing A1/A2 astrocyte induction and astrocyte transcriptome changes in the brain after TBI. 1b. Determining the role of microglia in A1 astrocyte induction in the brain after TBI. 1c. Determining neurotoxic ability of A1 astrocytes isolated from the brain after TBI. 1d. Establishing whether A1 astrocytes have a critical role in long-term neuropathology and functional outcome following TBI. Aim 2 would determine the therapeutic efficacy of targeting senescent A1 astrocytes and microglia as a potential therapy for TBI. This would be achieved by: 2a. Determining the therapeutic efficacy of senolytic drugs to ablate senescent A1 astrocytes and senescent microglia and reduce neuropathology and functional deficits long-term after TBI. 2b. Establishing the therapeutic window for senolytic drug treatment in TBI. 2c. Determining the duration of beneficial effects for senolytic drugs in TBI. The proposed research is highly innovative conceptually in proposing a critical role of recently identified A1 astrocytes and senescent cells in TBI pathology and chronic neuroinflammation. It is also highly innovative technically in the proposed use of a novel triple-knockout mouse model of the three A1-inducing factors, RNA-seq for glial cell transcriptome profiling, and the proposed use of recently identified senolytics as potential therapies to improve long-term outcome in TBI. If successful, the studies would have high impact on the field as they could provide hope of a therapy that could be used months or even years after TBI, where there is now no treatment options other than supportive care.