Ephrins regulate stem cell proliferation following TBI

Ephrins 调节 TBI 后干细胞增殖

• 批准号: 7106557
• 负责人: Daniel Jon Liebl
• 金额: $ 30.58万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106557
• 关键词: brain injury; cell growth regulation; cell migration; cell proliferation; ephrins; gel electrophoresis; gene targeting; genetically modified animals; green fluorescent proteins; immunoprecipitation; in situ hybridization; laboratory mouse; molecular /cellular imaging; polymerase chain reaction; protein structure function; receptor expression; regeneration; stem cells; tissue /cell culture; trauma; western blottings

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.

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。大多数 TBI 研究重点关注影响病理发生的因素，而很少有研究探讨促进康复的机制。与 TBI 相关的细胞损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明确，甚至更少人知道 TBI 后功能如何改变。该提案中概述的研究将检查一系列分子、Ephrins 及其受体（Eph 受体），这些分子与中枢神经系统的整个发育过程有关。我们最近证明这些分子也在成体干/祖细胞、成体神经母细胞和周围组织中表达。 我们假设 ephrinB3 可能 具有阻止细胞周期并进而促进有丝分裂后分化的功能。 此外，损伤后 ephrinB3 和/或其受体的过度表达可能会限制内源干/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脑室下区（SVZ）内的功能。 本申请的目标 1 将研究它们在调节 SVZ 内源性成体干细胞/祖细胞增殖中的功能，以及 ephrinB3 的缺失是否会改变细胞周期蛋白浓度。 目标 2 将采用体外测定来检查 ephrinB3 的作用机制和用于调节细胞周期停滞的信号通路。 目标 3 将检查 ephrinB3 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 ephrinB3 及其受体调节正常和受伤大脑中干细胞/祖细胞增殖的功能的重要机制信息，并可能导致促进慢性损伤患者康复的治疗方法。