Mechanisms of Chronic Progressive Axon Degeneration Following TBI

TBI 后慢性进行性轴突变性的机制

• 批准号: 10684183
• 负责人: Victoria Eleanor Johnson
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684183
• 关键词: Acute; Address; Alzheimer' s Disease; Animal Model; Atrophic; Autopsy; Axon; Brain; Brain Concussion; Cell Death; Cell Survival; Cells; Chronic; Chronic Phase; Complex; Cytoskeleton; Data; Development; Diffuse Axonal Injury; Diffuse Brain Injury; Dropout; Family suidae; Focal Brain Injuries; Functional disorder; Health; Human; Impaired cognition; Individual; Injury; Interruption; JUN gene; Lesion; Light; Measurement; Mechanics; Modeling; Mus; Nature; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phase; Phenotype; Phosphotransferases; Process; Reporting; Retrograde Degeneration; Role; Sampling; Secondary to; Serum; Signal Pathway; Signal Transduction; Sports; Swelling; Synapses; Syndrome; TBI Patients; Techniques; Therapeutic Intervention; Time; Tissue Sample; Tissues; Tracer; Trauma; Traumatic Brain Injury; Viral; axonal degeneration; behavioral outcome; cell injury; design; functional decline; human tissue; injured; neural network; neurofilament; neuron loss; neuropathology; new therapeutic target; novel; postsynaptic; postsynaptic neurons; pre-clinical; single cell sequencing; single-cell RNA sequencing; targeted treatment; three-dimensional visualization; translational model; translational study; white matter; white matter injury

PROJECT SUMMARY/ ABSTRACT Moderate or severe TBI is a substantial health problem that in addition to often-devastating acute effects, can trigger chronic and evolving neuropathologies that may underlie long-term functional decline. Surprisingly protracted axonal degeneration and associated tissue atrophy has be observed following moderate-severe TBI in humans, persisting many months and years after injury and may contribute to progressive cognitive decline in some patients. However, the mechanisms that drive axons to continue to swell and degenerate in the months and years post-TBI are unknown, and potentially modifiable. Moreover, how the acute injury, including the degree of focal versus diffuse brain injury, contributes to the nature and progression of axon degeneration is unexplored. Here we hypothesize that chronic axon degeneration in moderate-severe TBI reflects a progressive disconnection syndrome across neural networks via degeneration in both an anterograde and retrograde direction, which is dependent upon the nature and distribution of the initial injury. The death of neuronal somata, for example due to a focal lesion, can induce downstream (anterograde) degeneration of their efferent axons (and potentially their synaptic partners) and has long been thought as the dominant driver of axon loss in the subacute phase. In contrast, loss of a neuron's post-synaptic partner has been shown to drive retrograde degeneration via the loss of survival signaling (via the Jun Kinase/ c-Jun pathway). In preliminary data we provide evidence that both retrograde and anterograde degeneration drive chronic and progressive axon degeneration for many months and years post-TBI using multiple models and post-mortem human TBI tissue. Based on these compelling findings we propose an integrated translational design to 1) Determine the relative contribution and mechanisms of anterograde and retrograde degeneration chronically post-TBI in mice via examination of the neuronal network through tissue clearing techniques in combination with viral tracing and single cell RNA sequencing; 2) Utilize a gyrencephalic model of TBI to validate observations in mice and evaluate how progressive axon degeneration across the gyrencephalic brain determines behavioral outcome and, 3) Determine the role of focal and diffuse brain injuries in determining the extent, distribution and nature of progressive axon degeneration following human TBI using post-mortem samples. Understanding the mechanisms by which axons degenerate in the chronic phase post-injury will provide important data necessary for the development of targeted therapeutic interventions over time following TBI.

项目摘要/摘要 中度或重度TBI是一个严重的健康问题，除了通常具有破坏性的急性影响外，还可能引发慢性和不断发展的神经病理学，这些神经病理学可能是长期功能下降的基础。令人惊讶的是，在人类中重度TBI后观察到了持久的轴突变性和相关的组织萎缩，在损伤后持续数月和数年，并且可能导致一些患者的进行性认知下降。然而，驱动轴突在TBI后数月和数年内继续膨胀和退化的机制是未知的，并且可能是可修改的。此外，急性损伤，包括局灶性与弥漫性脑损伤的程度，如何有助于轴突变性的性质和进展是未知的。 在这里，我们假设中重度TBI的慢性轴突变性反映了通过顺行和逆行方向的变性跨越神经网络的进行性断开综合征，这取决于初始损伤的性质和分布。神经元胞体的死亡，例如由于局灶性病变，可以诱导其传出轴突（以及潜在的其突触伴侣）的下游（顺行）变性，并且长期以来被认为是亚急性期轴突损失的主要驱动因素。相比之下，神经元突触后伴侣的丧失已被证明通过存活信号传导的丧失（通过Jun激酶/ c-Jun途径）驱动逆行变性。在初步数据中，我们使用多种模型和死后人类TBI组织提供了逆行和顺行变性驱动TBI后数月和数年的慢性和进行性轴突变性的证据。基于这些令人信服的发现，我们提出了一种整合的翻译设计，以1）通过组织清除技术结合病毒追踪和单细胞RNA测序检查神经元网络，确定小鼠TBI后慢性顺行和逆行变性的相对贡献和机制; 2）利用TBI的脑回模型来验证小鼠中的观察结果，并评估跨脑回脑的进行性轴突变性如何决定行为结果，3）使用死后样本确定局灶性和弥漫性脑损伤在确定人TBI后进行性轴突变性的程度、分布和性质中的作用。 了解损伤后慢性期轴突退化的机制将为TBI后随着时间的推移开发靶向治疗干预提供重要数据。