Neurogranin and Traumatic Brain Injury

神经粒蛋白和创伤性脑损伤

• 批准号: 10512044
• 负责人: C EDWARD DIXON
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512044
• 关键词: Acute; Alzheimer' s Disease; Anatomy; Animal Model; Animals; Attention; Attenuated; Behavior; Behavioral; Biological Markers; Blood; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Binding; Calmodulin; Chronic; Circulation; Cognition; Cognitive deficits; Communication; Complex; Data; Dendritic Spines; Economic Burden; Electrophysiology (science); Experimental Models; FDA approved; Functional disorder; Hippocampus; Hospitalization; Impaired cognition; Impairment; Injury; Investigation; Learning; Mediating; Medical Care Costs; Memory; Military Personnel; Modeling; Molecular; Molecular Conformation; Molecular Target; Morphology; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Pathologic; Pathway interactions; Performance; Pharmacotherapy; Phosphorylation; Physical Function; Plasma; Protein Kinase C; Proteins; Rattus; Regulation; Reporting; Research; Role; Serum; Severities; Signal Transduction; Symptoms; Synapses; Synaptic plasticity; Syndrome; Therapeutic; Time; Traumatic Brain Injury; Tretinoin; Veterans; Viral; Vitamin A; adeno-associated viral vector; behavioral outcome; calmodulin-dependent protein kinase II; cognitive function; cognitive task; combat; controlled cortical impact; density; disability; emotional functioning; exosome; experience; functional outcomes; high risk; improved; injured; ischemic injury; mild traumatic brain injury; nervous system disorder; neurogranin; neuron loss; neuropathology; overexpression; postsynaptic; pre-clinical; protein expression; therapeutic biomarker; therapeutic target

Deployed and nondeployed military personnel are at higher risk of traumatic brain injury (TBI) than civilians. TBI of all severities can result in chronic disturbances of cognitive, behavioral, emotional, and physical functioning. Learning, memory and attention are especially vulnerable across the spectrum of TBI injury severity and symptoms may persist years to decades. While most TBIs experienced by Veteran’s are mild, enduring a severe TBI produces significant personal, societal and economic burden. TBIs that require hospitalization account for approximately 90% of total TBI medical costs. There are currently no FDA-approved pharmacotherapies to treat TBI. Thus, research to develop new pharmacotherapies for TBI will benefit Veterans with persistent posttraumatic neurocognitive disabilities. These impairments have been recapitulated in pre- clinical TBI models. Animals demonstrate poor performance on cognitive tasks along with associated pathological synaptic communication on molecular, anatomical and electrophysiological scales. Furthermore, these models for the investigation of underlying cellular mechanisms and potential therapeutic targets of TBI associated impairments. Synaptic strength and plasticity are believed to underlie learning and memory behaviors. Dysfunction of synapses is one of the earliest and most common abnormalities preceding neuronal death in neurodegenerative diseases and has been reported in several animal models of TBI. Neurogranin (Ng), a post-synaptic protein localized to post-synaptic dendritic spines, notably regulates synaptic plasticity through calcium-dependent temporal and spatial regulation of calmodulin (CaM). Synaptic activity leads to precisely timed changes in Ng phosphorylation by protein kinase C (PKC). This is synchronized with Ca2+-CaM downstream signaling and Calcium-Calmodulin Kinase II (CaMKII) activation via autophosphorylation. Ng modulates synaptic excitability through these pathways. CSF and blood levels of Ng have also been used as biofluid biomarkers of synaptic neurodegeneration in Alzheimer’s disease and other neurodegenerative syndromes, as well as in acute TBI. Recently, chronic decreases in plasma exosome levels of Ng was seen in combat-deployment-related mild TBI. Our recent findings showed significantly reduced Ng protein expression in the rat cortex and hippocampus up to two weeks after controlled cortical impact, particularly in the CA1 and CA3 of the hippocampus. This evidence suggests Ng’s potential involvement in pathological mechanisms of learning and memory difficulties after TBI. The overall hypothesis is that decreased Ng expression contributes to dysfunctional synaptic plasticity and cognition after TBI. Specific Aim 1 will examine the effects of TBI on Ng signaling, associated synaptic proteins and dendritic morphology. Preliminary data shows Ng is detectable in serum in sham and CCI-injured animals at two weeks post-injury. Thus, for the first time, an experimental model can be utilized to directly study the relationship between biofluid Ng levels and conformational synaptic neuropathology. Specific Aim 2 will next examine using adeno-associated viral (AAV) delivery to increase neuronal Ng in the hippocampus. Retinoic acid (RA), a metabolite of Vitamin A, increases Ng protein levels and has been identified as a potential pharmacotherapeutic for ischemic injury and other neurological disorders. Specific Aim 3 will determine the effects of RA therapy on Ng signaling, synaptic neurodegeneration, and cognitive function after TBI. Successful completion of this study will identify Ng as a therapeutic target and biomarker of synaptic dysfunction in TBI.

已部署和未部署的军事人员发生创伤性脑损伤的风险高于 平民。所有严重的脑外伤都会导致认知、行为、情绪和身体的慢性障碍。 功能正常。在各种颅脑损伤严重程度中，学习、记忆和注意力尤其脆弱 而且症状可能会持续几年到几十年。虽然退伍军人经历的大多数颅脑损伤都是轻微的，但 严重的创伤会造成严重的个人、社会和经济负担。需要住院的重型颅脑损伤 约占TBI医疗总成本的90%。目前没有FDA批准的 治疗脑外伤的药物疗法。因此，研究开发脑损伤的新药物疗法将使退伍军人受益 患有持续性创伤后神经认知障碍。这些损害已经在Pre- 临床脑外伤模型。动物在认知任务中表现出较差的表现以及相关的 在分子、解剖和电生理尺度上的病理性突触通讯。此外， 这些模型用于研究脑外伤的潜在细胞机制和潜在的治疗靶点 相关的损害。 突触的强度和可塑性被认为是学习和记忆行为的基础。失调症 突触是神经退行性变中神经元死亡前最早和最常见的异常之一。 并已在几种脑外伤动物模型中得到报道。突触后蛋白神经颗粒素(Ng) 定位于突触后树突棘，通过钙依赖显著调节突触可塑性 钙调素(CaM)的时空调控。突触活动导致Ng的精确计时变化 蛋白激酶C(PKC)的磷酸化。这与钙离子-钙调素下游信号同步，并 钙-钙调蛋白激酶II(CaMKII)通过自身磷酸化激活。NG对突触兴奋性的调节作用 通过这些小路。脑脊液和血液中Ng的水平也被用作突触的生物流体生物标志物 阿尔茨海默病和其他神经退行性综合征的神经退行性变，以及急性脑外伤。 最近，在与战斗部署相关的轻度脑损伤中，血浆Ng外切体水平出现慢性下降。 我们最近的研究结果显示，Ng蛋白在大鼠大脑皮质和海马区的表达显著减少， 受控皮质撞击后两周，尤其是在海马区的CA1和CA3。这一证据 提示Ng可能参与了脑外伤后学习记忆障碍的病理机制。 总体假设是Ng表达减少与突触可塑性障碍有关 和脑损伤后的认知功能。具体目标1将研究脑损伤对NG信号、相关突触的影响 蛋白质和树突形态。初步数据显示，在假手术和CCI损伤的血清中可检测到Ng 动物于伤后两周取材。因此，首次可以利用实验模型来直接研究 生物体液Ng水平与构象突触神经病理的关系接下来是《特定目标2》 研究使用腺相关病毒(AAV)递送来增加海马区神经元Ng。维甲酸 维生素A的代谢物(RA)可提高Ng蛋白水平，已被认为是一种潜在的 对缺血性损伤和其他神经疾病的药物治疗。具体目标3将决定 RA治疗对脑外伤后NG信号、突触神经退行性变和认知功能的影响。成功 这项研究的完成将确定Ng是脑外伤患者突触功能障碍的治疗靶点和生物标志物。