SNARE Proteins and TBI

描述(申请人提供)：创伤性脑损伤(TBI)可导致认知、行为、情绪和身体功能障碍。正常的大脑认知功能依赖于通过神经递质释放的突触交流。颅脑损伤可导致多巴胺能和胆碱能神经递质释放的持续性缺陷，但其机制尚不清楚。突触的神经递质释放需要突触小泡与突触前质膜的融合。在这一过程中的一个关键步骤是组装一个可溶的N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合体，它是一个高度稳定的平行四股螺旋结构，位于突触小泡SNARs Synaptobrevin 2(Syb2)和质膜SNARs Synaxin 1和25 kDa突触体相关蛋白(SNAP-25)之间。SNARE蛋白的病理可能在脑损伤中起重要作用，特别是在神经传递和随后的认知障碍方面。半胱氨酸串蛋白α(CSP)在突触活动过程中通过陪伴SNAP-25促进SNARE-复合体的组装。最近发现，锂在与治疗相关的浓度下，可以增强CSP的表达。这代表了一种新的机制，锂可以通过它来恢复脑损伤后神经递质释放的缺陷。为了进一步评估CSP在介导锂对脑外伤后SNARE蛋白和认知恢复的影响中的作用，本项目将在CSP转基因小鼠中评估锂治疗。这项建议的目的是研究脑外伤后神经传递障碍的陷阱复杂机制。总的假设是，脑外伤后的认知障碍可能至少部分归因于突触陷阱复合体形成的障碍和随后的神经递质释放障碍。具体目标1将研究TBI对单个SNARE蛋白、SNARE-复合体组装和SNARE-复合体组装的关键调节因子CSP的影响。具体目标2将确定锂增加CSP的表达是否与微透析测量的SNARE-Complex组装和诱发的神经递质释放的恢复有关。具体目标3将确定锂是否可以减轻脑外伤后的认知障碍。这个项目的成功完成可能提供证据，证明颅脑损伤后圈套复合体减少，并确定锂在治疗创伤后认知障碍方面的新应用。 公共卫生相关性：在美国，每年约有170万人遭受创伤性脑损伤(TBI)，超过530万人患有由创伤性脑损伤造成的残疾。在这项研究中，我们将探索一种新的创伤后认知障碍的机制，并将评估锂治疗作为一种对策。如果成功，这项研究 将导致FDA批准的治疗脑损伤后记忆障碍的药物的新用途的开发。

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) can result in the disturbance of cognitive, behavioral, emotional, and physical functioning. Normal brain cognitive function depends on synaptic communication via neurotransmitter release. TBI can produce persistent deficits in both dopaminergic and cholinergic evoked neurotransmitter release, but the mechanisms are unknown. Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. A crucial step in this process involves the assembly of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, a highly stable, parallel four-helix bundle formed between the synaptic vesicle SNARE synaptobrevin 2 (syb2) and the plasma membrane SNAREs syntaxin 1 and synaptosome-associated protein of 25 kDa (SNAP-25). The pathology of SNARE proteins may play an important role in TBI, especially concerning neurotransmission and subsequent cognitive disturbances. Cysteine string protein alpha (CSP¿) promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. It has recently been discovered that lithium, at therapeutically relevant concentrations, can enhance the expression of CSP¿. This represents a novel mechanism by which lithium may restore neurotransmitter release deficits after TBI. To further evaluate the role of CSP¿ in mediating lithium's effect on SNARE proteins and cognitive recovery after TBI, this project will evaluate lithium therapy in a CSP¿ transgenic mouse. The goal of this proposal is to examine SNARE-complex mechanisms of neurotransmission deficits after TBI. The overall hypothesis is that cognitive deficits following TBI may be, at least partialy, attributable to impairment in synaptic SNARE-complex formation and subsequent neurotransmitter release deficits. Specific Aim 1 will examine the effects of TBI on individual SNARE proteins, SNARE- complex assembly, and CSP¿, a key regulator of SNARE-complex assembly. Specific Aim 2 will determine if increasing the expression of CSP¿ by lithium is associated with a restoration of SNARE-complex assembly and evoked neurotransmitter release as measured by microdialysis. Specific Aim 3 will determine if lithium can attenuate cognitive deficits after TBI. Successful completion of this project may provide evidence that SNARE-complexes are diminished after TBI and identify a novel application of lithium for the treatment of posttraumatic cognitive deficits. PUBLIC HEALTH RELEVANCE: Approximately 1.7 million people sustain traumatic brain injury (TBI) each year in the United States and more than 5.3 million people live with disabilities caused by TBI. In this study, we will investigate a new mechanism of cognitive post-traumatic cognitive deficits and will evaluate lithium therapy as a countermeasure. If successful, this study would lead to the development of a new use for an FDA-approved drug for the treatment of memory deficits after TBI.