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: 10440849
• 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/10440849
• 关键词: 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; 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; TNF gene; 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; neurotoxic; novel; novel therapeutics; preclinical study; progressive neurodegeneration; release factor; senescence; stressor; therapeutic evaluation; therapeutic target; transcriptome; transcriptome sequencing; 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.

在美国，创伤性脑损伤是导致死亡和残疾的主要原因之一。 研究表明，颅脑损伤后存在慢性神经炎症，这有助于进展 神经退行性变、白质丢失和认知能力下降。不幸的是，病理过程 人们对潜在的慢性神经炎知之甚少。目前研究的总体目标是 阐明脑外伤后慢性神经炎的发病机制及试验治疗 针对这些机制的干预。我们的中心假设是，新发现的 促炎和神经毒性A1星形胶质细胞在慢性神经炎症中发挥关键作用，进行性 脑外伤后长期神经退行性变和认知功能减退。A1星形胶质细胞是指失去 有能力执行其正常功能，产生补体成分，较不能促进 新突触的形成，以及可以破坏或杀死神经元和少突胶质细胞的释放因子[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，增加了衰老药物可能被用于消融A1星形胶质细胞的可能性 在脑外伤中的治疗。为了检验我们的假设，我们提出了以下具体目标。目标1将描述 A1星形胶质细胞在脑损伤中的诱导、机制及作用。这将通过以下方式实现：1. 脑创伤后星形胶质细胞A1/A2诱导及转录组变化的特征。1B. 确定小胶质细胞在脑创伤后A1星形胶质细胞诱导中的作用。1C。测定神经毒性 脑外伤后脑组织分离的A1星形胶质细胞的能力。1D。确定A1星形胶质细胞是否具有 对脑外伤后长期神经病理和功能结果的关键作用。目标2将决定 靶向衰老的A1星形胶质细胞和小胶质细胞作为脑外伤潜在治疗方法的疗效。这 将在：2a之前实现。促衰老药物消融衰老A1的疗效测定 脑损伤后远期的星形胶质细胞和衰老的小胶质细胞，减少神经病理和功能缺陷。 2B。建立脑损伤抗过敏药物治疗的治疗窗口。2C。确定持续时间 抗衰老药物在颅脑损伤中的有益作用。拟议的研究在概念上具有很高的创新性 提出最近发现的A1星形胶质细胞和衰老细胞在脑外伤病理和慢性脑损伤中的关键作用 神经炎。它在技术上也具有很高的创新性，建议使用一种新颖的三重击倒 三种A1诱导因子的小鼠模型，胶质细胞转录组图谱的RNA-seq，以及 建议使用最近确定的感觉神经降解剂作为潜在的治疗方法来改善脑外伤的长期结果。如果 如果成功，这些研究将对该领域产生重大影响，因为它们可能提供一种治疗方法的希望 可在创伤性脑损伤后数月甚至数年使用，目前除支持性治疗外没有其他治疗选择 关心。