ROLE OF EPHRINS & EPH IN REGULATING SYNAPTOGENESIS AFTER TRAUMATIC BRAIN INJURY

目前有500万美国人因创伤性脑损伤(TBI)而生活残疾。脑外伤的研究大多集中在影响发病的因素上，而对促进康复的机制的研究较少。了解中枢神经系统(CNS)中调节生长和可塑性的机制将为促进脑创伤后的再生提供基本依据。这项建议中概述的研究将检查一系列分子，肾上腺素及其受体(Eph受体)，这些分子与整个发育中的中枢神经系统的发育模式、轴突引导和颤动、中线发育和突触可塑性有关。我们最近证实，这些分子也可能对受损的中枢神经系统的生长和可塑性起到调节作用。我们将使用基因靶向的基因敲除小鼠来研究它们在海马体精确回路中的功能。本应用的目的1将研究它们在调节苔藓纤维轴突生长、树突生长和突触可塑性中的作用。AIM 2和AIM 3将评估脑外伤后EPhin和Eph受体的功能。我们将首先在一个已建立的轻度(3.5m/S)受控皮质撞击脑损伤模型中检验这些联系，因为它们与海马体功能障碍有关。然后，我们将研究肾上腺素和Eph受体是否起到调节苔藓纤维传入再生的作用。这些研究将提供关于调节脑外伤后再生的机制的基本信息，并可能导致促进慢性损伤患者康复的治疗方法。

Five million Americans are presently living with disability as a result of traumatic brain injury (TBI). The majority of TBI research focuses on the factors that influence the onset of pathology, while fewer studies have addressed the mechanisms that promote recovery. Understanding the mechanisms that function to regulate growth and plasticity in the central nervous system (CNS) will provide the fundamental basis for promoting regeneration following TBI. The studies outlined in this proposal will examine a family of molecules, Ephrins and their receptors (Eph receptors), which have been implicated in developmental patterning, axonal guidance and fasciculation, midline development, and synaptic plasticity throughout the developing CNS. We have recently demonstrated that these molecules may also function to regulate growth and plasticity in the injured CNS. We will employ gene-targeted knockout mice to investigate their functions within the precise circuitry of the hippocampus. Aim 1 of this application will investigate their function in regulating mossy fiber axonal growth, dendritic growth, and synaptic plasticity. Aim 2 and Aim 3 will evaluate Ephrin and Eph receptor function following TBI. We will first examine these connections in an established model of mild (3.5 m/s) controlled cortical impact brain injury as they relate to hippocampal dysfunction. We will then examine whether Ephrins and Eph receptors function to mediate regrowth of mossy fiber afferents. These studies will provide essential information on the mechanisms that function to regulate regeneration following TBI, and could lead to therapeutic treatments to promote recovery in the chronically injured patient.