Preso调控突触后支架蛋白复合体在创伤性脑损伤中的作用及机制研究

Traumatic brain injury has high incidence and morbidity, which is a major cause of death in young people. Although there are a lot of laboratory and clinical investigations on traumatic brain injury, molecular mechanism underlying traumatic brain injury is still unclear and drug treatment in clinical practice is limited. Previous studies indicated that glutamate receptors (NMDAR) and scaffold proteins (PSD-95) in postsynaptic density (PSD) played crucial roles in regulation of neuronal injury and traumatic brain injury. On the basis of established research platform for traumatic brain injury, proposer plan to elucidate the molecular mechanism underlying Preso in regulating postsynaptic scaffold protein complexes (NMDAR/PSD-95/nNOS)-associated signal pathways by using down-regulation/ up-regulation of Preso, a postsynaptic protein, via lentivirus transfection in cultured neurons and mice. This subject on Preso and its related signal pathways is to investigate the mechansim of traumatic brain injury in vitro and in vivo. It is expected to further establish the postsynaptic signaling network, clarify the pathological mechanism for traumatic brain injury, and provide novel drug targets and treatment strategies for traumatic brain injury.

创伤性脑损伤发生率高、致残率高，是导致青壮年死亡的主要原因。虽然针对创伤性脑损伤开展了大量的基础和临床研究，但创伤性脑损伤后的分子病理机制尚未完全阐明，并缺乏有效的临床药物干预措施。以往研究和申请人前期研究表明，突触后致密物质（PSD）中的谷氨酸受体（NMDAR）和支架蛋白（PSD-95）在神经损伤和创伤性脑损伤的调控过程中发挥关键作用。本课题拟利用已建立的创伤性脑损伤研究平台，分别在离体培养神经元和小鼠上通过慢病毒载体转染上调/下调突触后蛋白Preso的表达，明确Preso在创伤性脑损伤中的作用，阐明Preso调控突触后支架蛋白复合体（NMDAR/PSD-95/nNOS）信号通路的机制。本课题以Preso及相关信号通路为切入点，在体内外研究创伤性脑损伤的调控机制，有望进一步建立突触后信号分子调控网络，明确创伤性脑损伤后的分子病理机制，为创伤性脑损伤治疗提供新靶点和新策略。

创伤性脑损伤（TBI）发生率高、致残率高，是导致青壮年死亡的主要原因。虽然针对TBI开展了大量的基础和临床研究，但TBI后的分子病理机制尚未完全阐明，并缺乏有效的临床药物干预措施。以往研究和申请人前期研究表明，突触后致密物质中的谷氨酸受体和突触后支架蛋白形成复合体，在TBI调控过程中发挥关键作用。本项目利用已建立的TBI研究平台，首次证实新型突触后支架蛋白Preso在TBI后的变化规律和作用。并进一步证实，Preso主要通过影响NMDAR功能干预TBI后的神经元兴奋性毒性损伤。在此基础上，本项目探索Preso对NMDAR/PSD-95/nNOS复合体的调控效应，证实Preso主要调节NMDAR/PSD-95/nNOS复合体的稳定性，进而影响TBI后神经元线粒体功能和氧化应激反应。本项目的研究成果，为深入探索TBI后的神经元病理机制提供了新的理论依据，并将突触后支架蛋白作为新的药物干预靶点，为TBI的救治提供了新策略，具有重要的临床意义。