Mechanisms and Therapeutic Targeting of Chronic Neuroinflammation in Traumatic Brain Injury

创伤性脑损伤中慢性神经炎症的机制和治疗靶向

• 批准号: 10576964
• 负责人: DARRELL W BRANN
• 金额: $ 38.5万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576964
• 关键词: Ablation; Acute; Agonist; Alzheimer' s Disease; Astrocytes; Brain; Brain Injuries; Brain region; Cause of Death; Cell Death; Cells; Chronic; Chronic Disease; Complement; Complement 1q; Data; GLP-I receptor; Health; Huntington Disease; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-1 alpha; Ischemia; Knockout Mice; Light; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Outcome; Parkinson Disease; Pathologic Processes; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Play; Research; Resistance; Role; Supportive care; Synapses; TBI treatment; Testing; Therapeutic; Therapeutic Intervention; Trauma; Traumatic Brain Injury; Treatment Efficacy; United States; Work; cell injury; disability; dopaminergic neuron; functional decline; functional outcomes; improved; innovation; mouse model; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxic; novel; novel therapeutics; preclinical study; progressive neurodegeneration; release factor; senescence; stressor; therapeutic evaluation; therapeutic target; transcriptome; transcriptome sequencing; transcriptomic profiling; white matter; white matter damage

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.

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 后会出现慢性神经炎症，这会导致进行性脑损伤。 神经退行性变、白质损失和认知能力下降。不幸的是，病理过程 潜在的慢性神经炎症尚不清楚。当前研究的总体目标是 阐明 TBI 后慢性神经炎症的机制并测试治疗方法 针对这些机制的干预措施。我们的中心假设是新发现的 促炎性和神经毒性 A1 星形胶质细胞在慢性神经炎症、进行性炎症中发挥关键作用 TBI 后长期神经退行性变和认知能力下降。 A1星形胶质细胞是失去 执行其正常功能、产生补体成分的能力，不太能够促进 新突触的形成，并释放可以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，并且 衰老，增加了衰老药物可用于消除 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、潜在机制和作用。这可以通过以下方式实现： 1a． 表征 TBI 后大脑中 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 后大脑 A1 星形胶质细胞诱导中的作用。 1c.确定神经毒性 TBI 后从大脑中分离出的 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发挥关键作用。目标 2 将确定 靶向衰老 A1 星形胶质细胞和小胶质细胞作为 TBI 潜在疗法的治疗效果。这 将通过以下方式实现： 2a.确定抗衰老药物消除衰老 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 的 senolytic 药物治疗的治疗窗口。 2c.确定持续时间 抗衰老药物对 TBI 的有益作用。所提出的研究在概念上具有高度创新性 提出最近发现的 A1 星形胶质细胞和衰老细胞在 TBI 病理学和慢性病中的关键作用 神经炎症。它在技术上也具有高度创新性，建议使用新颖的三重敲除技术 三种 A1 诱导因子的小鼠模型、用于神经胶质细胞转录组分析的 RNA-seq 以及 建议使用最近发现的 senolytics 作为改善 TBI 长期结果的潜在疗法。如果 成功的话，这些研究将对该领域产生重大影响，因为它们可以为治疗带来希望 可以在 TBI 后数月甚至数年使用，目前除了支持性治疗外没有其他治疗选择 关心。

项目成果

Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice.

• DOI: 10.3389/fnins.2023.1227705
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Wang, Jing;Lu, Yujiao;Carr, Christopher;Dhandapani, Krishnan M.;Brann, Darrell W.
• 通讯作者: Brann, Darrell W.