REGULATION OF SYNAPTIC FORMATION & EFFICACY FOLLOWING TRAUMATIC BRAIN INJURY

目前有700万美国人因创伤性脑损伤（TBI）而残疾， 每年有50万新病人入院。TBI是一种毁灭性的残疾， 功能障碍、学习和记忆障碍以及认知缺陷。在受伤时，这些缺陷 导致局灶性细胞损失，然而，损害不限于该直接区域。事实上，TBI通常会导致 包括反应性神经胶质细胞和突触功能障碍。我们的研究旨在 研究反应性星形胶质细胞在TBI后调节突触功能中的作用。我们假设肝配蛋白 Eph受体在星形胶质细胞和突触前/后末梢之间的体内平衡中起作用。 在TBI后，我们认为ephrin和Eph受体的功能是调节突触的稳定性和可塑性。到 为了解决这一假设，我们将采用转基因小鼠的体外和体内方法。 具体来说，目的1将研究Ephrin和Eph受体在调节星形胶质细胞合成和 在正常和牵张损伤的体外条件下释放谷氨酸、D-丝氨酸和信号中间体。 这些分子是星形胶质细胞调节突触稳态的重要方面。目标2将检查 当生长在单层假或损伤星形胶质细胞上时，突触的形成和功能是否不同， 以及通过使用遗传突变的星形胶质细胞和/或神经元来检查ephrins/Eph受体的作用。 最后，目标3将通过检查我们的发现如何转化为复杂的CNS环境， 突触形成/功能和星形细胞功能，使用获得和丧失功能的方法和体内 控制性皮质撞击伤总之，我们的研究对于确定肝配蛋白和 Eph受体是突触形成的关键调节因子，在三突触相互作用中发挥作用， 星形胶质细胞突触前和突触后末梢 相关性（参见说明）; 请参阅建议书第“2”页，了解项目与公共卫生的整体相关性。

Seven million Americans are presently living with disability as a result of traumatic brain injury (TBI) with 500,000 new patients admitted every year. TBI is a devastating disability that leads to sensory and motor dysfunction, learning and memory impairment, and cognitive deficits. At the point of injury, these defects result in focal cell losses, however, damage is not limited to this immediate region. In fact, TBI often results in global changes that include reactive glial cells and synaptic dysfunction. Our studies are designed to examine the role of reactive astrocytes in regulating synaptic function after TBI. We hypothesize that ephrins and Eph receptors function in the homeostasis between the astrocytes and pre-/post-synaptic terminals. Following TBI, we believe ephrins and Eph receptors function to regulate synaptic stability and plasticity. To address this hypothesis, we will employ both in vitro and in vivo approaches using genetically modified mice. Specifically, aim 1 will examine the role of ephrins and Eph receptors in regulating astrocytes synthesis and release of glutamate, D-serine, and signaling intermediates in normal and stretch-injured in vitro conditions. These molecules are an important aspect of astrocyte regulated synaptic homeostasis. Aim 2 will examine whether synaptic formation and function differ when grown on a monolayer of sham or injured astrocytes, as well as examining the role of ephrins/Eph receptor by using genetically mutant astrocytes and/or neurons. Finally, aim 3 will examine how our findings translate to the complex CNS environment by examining synaptic formation/function and astocyte functions using gain and loss-of-function approaches and an in vivo controlled cortical impact injury. In summary, our studies are important in determining whether ephrins and Eph receptors are key regulators of synaptic formation and function in the tri-synaptic interactions between astrocytes, pre- and post-synaptic terminals. RELEVANCE (See instructions); Please refer to proposal page '2' for overall project relevance to public health.