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。与脑外伤相关的细胞丢失是需要克服的重大障碍，干细胞移植和细胞再生的最新进展为康复提供了一种潜在的治疗方法。然而，调控干细胞功能的机制仍然不明确，更不清楚脑损伤后这些功能是如何改变的。这项提案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)，它们与整个发育中的中枢神经系统有关。我们最近已经证明，这些分子也在成体干细胞/祖细胞、成体神经母细胞和周围组织中表达。我们假设ePhin B3可能 阻止细胞周期，进而促进有丝分裂后分化。此外，损伤后ewitinB3和/或其受体的过度表达可能限制内源性干/祖细胞的增殖能力。我们将使用基因靶向敲除小鼠来研究它们在脑室下区(SVZ)的功能。该应用的目的1将研究它们在调节SVZ内源性成体干细胞/祖细胞增殖中的作用，以及ewitinB3的缺失是否会改变细胞周期蛋白的浓度。Aim 2将采用体外实验方法来研究ewitinB3的作用机制以及用于调节细胞周期停滞的信号通路。目的3将研究EPhin B3及其Eph受体(S)在脑外伤后控制细胞增殖中的作用。这些研究将提供必要的机制信息，了解ephinB3及其受体(S)在调节正常和损伤脑内干/祖细胞增殖中的作用，并可能导致促进慢性损伤患者康复的治疗方法。

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.