Neurogranin and Traumatic Brain Injury

部署和未部署的军事人员的创伤性脑损伤（TBI）风险高于 平民所有严重程度的TBI都可能导致认知、行为、情绪和身体的慢性障碍。 功能学习、记忆和注意力在TBI损伤严重程度的范围内尤其脆弱 症状可能持续数年至数十年。虽然退伍军人经历的大多数TBI都是温和的，但持续的 严重的TBI会产生重大的个人、社会和经济负担。需要住院治疗的TBI 占TBI总医疗费用的90%左右。目前没有FDA批准的 药物治疗TBI。因此，研究开发新的药物治疗TBI将有利于退伍军人 患有持续性创伤后神经认知障碍这些缺陷已在预- 临床TBI模型。动物在认知任务中表现不佳，沿着相关的 病理性突触通讯在分子、解剖学和电生理学的尺度上。此外，委员会认为， 这些模型用于研究TBI的潜在细胞机制和潜在治疗靶点 相关的损伤。 突触的强度和可塑性被认为是学习和记忆行为的基础。功能障碍 突触是神经退行性疾病中神经元死亡前最早和最常见的异常之一， 疾病，并已在几种TBI动物模型中报道。神经颗粒蛋白（Ng），一种突触后蛋白 定位于突触后树突棘，通过钙依赖性调节突触可塑性 钙调素（CaM）的时空调控。突触活动导致Ng的精确定时变化 通过蛋白激酶C（PKC）磷酸化。这与Ca 2 +-CaM下游信号传导同步， 钙-钙调蛋白激酶II（CaMKII）通过自磷酸化激活。NG调节突触兴奋性 通过这些途径。Ng的CSF和血液水平也已被用作突触的生物流体生物标志物。 在阿尔茨海默病和其他神经退行性综合征以及急性TBI中的神经退行性变。 最近，在战斗部署相关的轻度TBI中观察到Ng的血浆外泌体水平的慢性降低。 我们最近的研究结果表明，在大鼠皮层和海马中， 在控制皮质撞击后两周，特别是在海马的CA 1和CA 3。这一证据 提示Ng可能参与TBI后学习和记忆困难的病理机制。 总的假设是，Ng表达减少导致突触可塑性功能障碍 脑外伤后的认知功能具体目标1将检查TBI对Ng信号传导、相关突触的影响。 蛋白质和树突状形态。初步数据显示，在假手术和CCI损伤的血清中可检测到Ng 受伤后两周的动物。因此，第一次可以利用实验模型直接研究 生物流体Ng水平与构象突触神经病理学之间的关系。具体目标2将在 检查使用腺相关病毒（AAV）递送以增加海马中的神经元Ng。维甲酸 (RA)，维生素A的代谢产物，增加Ng蛋白水平，并已被确定为潜在的 用于缺血性损伤和其他神经系统疾病的药物。具体目标3将决定 RA治疗对Ng信号传导、突触神经变性和TBI后认知功能的影响。成功 本研究的完成将鉴定Ng作为TBI中突触功能障碍的治疗靶标和生物标志物。

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.