Ephrins regulate stem cell proliferation following TBI

描述（由申请人提供）： 目前有500万美国人因创伤性脑损伤（TBI）而残疾。大多数TBI研究集中在影响病理发生的因素上，而很少有研究涉及促进恢复的机制。与TBI相关的细胞损失是需要克服的重要障碍，干细胞移植和细胞再生的最新进展为恢复提供了潜在的治疗方法。然而，调节干细胞功能的机制仍然不清楚，更不知道TBI后功能如何改变。本提案中概述的研究将检查一系列分子，Ephrin及其受体（Eph受体），这些分子在整个发育中的CNS中都有牵连。我们最近已经证明，这些分子也表达在成人干/祖细胞，成人神经母细胞和周围组织。 我们假设ephrinB 3可能 其功能是阻止细胞周期并反过来促进有丝分裂后的分化。 此外，损伤后ephrinB 3和/或其受体的过度表达可能限制内源性干/祖细胞增殖的能力。 我们将采用基因靶向敲除小鼠来研究它们在室管膜下区（SVZ）内的功能。 本申请的目的1将研究它们在SVZ中调节内源性成体干/祖细胞增殖的功能，以及ephrinB 3的缺失是否可以改变细胞周期蛋白浓度。 目的2将采用体外试验来研究ephrinB 3的作用机制和用于调节细胞周期停滞的信号通路。 目的3将研究ephrinB 3及其Eph受体在TBI后控制细胞增殖中的作用。这些研究将提供有关ephrinB 3及其受体调节正常和受损脑中干/祖细胞增殖的功能的基本机制信息，并可能导致治疗性治疗以促进慢性损伤患者的恢复。

DESCRIPTION (provided by applicant): 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. Cellular loss associated with TBI is significant barrier to overcome, and recent advancements in stem cell transplantation and cellular rejuvenation provide a potential therapy for recovery. However, the mechanisms that regulate stem cell functions are still ill defined, and even less is known how the functions are altered following TBI. The studies outlined in this proposal will examine a family of molecules, Ephrins and their receptors (Eph receptors), which have been implicated throughout the developing CNS. We have recently demonstrated that these molecules are also expressed in adult stem/progenitor cell, adult neuroblasts and in surrounding tissues. We hypothesize that ephrinB3 may function to arrest cell cycle and in turn promote post-mitotic differentiation. Furthermore, following injury the over expression of ephrinB3 and/or its receptors may limit the ability of endogenous stem/progenitor cell to proliferate. We will employ gene-targeted knockout mice to investigate their functions within the subventricular zone (SVZ). Aim 1 of this application will investigate their function in regulating endogenous adult stem/progenitor cell proliferation in the SVZ, and whether the absence of ephrinB3 can alter cell cycle protein concentrations. Aim 2 will employ an in vitro assay to examine the mechanisms of action for ephrinB3 and signaling pathways used to regulate cell cycle arrest. Aim 3 will examine the role of ephrinB3 and its Eph receptor(s) in controlling cell proliferation following TBI. These studies will provide essential mechanistic information on the function of ephrinB3 and its receptor(s) to regulate stem/progenitor cell proliferation in the normal and injured brain, and could lead to therapeutic treatments to promote recovery in the chronically injured patient.