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)而生活残疾 每年新入院患者50万人。颅脑损伤是一种毁灭性的残疾，会导致感觉和运动 功能障碍，学习和记忆障碍，以及认知缺陷。在受伤的时候，这些缺陷 导致灶性细胞损失，然而，损害并不局限于这个紧邻的区域。事实上，TBI往往会导致 在包括反应性胶质细胞和突触功能障碍在内的全球变化中。我们的研究旨在 观察脑外伤后反应性星形胶质细胞在调节突触功能中的作用。我们假设伊弗林 而Eph受体在星形胶质细胞和突触前/突触后终末之间的动态平衡中起作用。 在脑损伤后，我们认为Eparins和Eph受体具有调节突触稳定性和可塑性的功能。至 为了解决这一假设，我们将使用转基因小鼠的体外和体内方法。 具体地说，目标1将研究肾上腺素和Eph受体在调节星形胶质细胞合成和 在体外条件下，谷氨酸、D-丝氨酸和信号中间体在正常和拉伸损伤条件下的释放。 这些分子是星形胶质细胞调节突触内稳态的一个重要方面。Aim 2将检查 当生长在假的或受损的星形胶质细胞的单层上时，突触的形成和功能是否不同，如 以及通过使用基因突变的星形胶质细胞和/或神经元来检测Eparins/Eph受体的作用。 最后，目标3将通过研究我们的发现如何转化到复杂的中枢神经系统环境 突触形成/功能和星形胶质细胞功能的获得和功能丧失方法以及体内 受控的皮质撞击损伤。总而言之，我们的研究对于确定依弗林和 EPH受体是突触形成和功能的关键调节者，在三者之间的突触相互作用 星形胶质细胞，突触前和突触后终末。 相关性(见说明)； 有关整个项目与公共卫生的相关性，请参阅提案页‘2’。

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.