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）：由于脑损伤（TBI），目前有500万美国人患有残疾人。大多数TBI研究都集中在影响病理开始的因素上，而较少的研究却解决了促进康复的机制。与TBI相关的细胞丧失是克服的重大障碍，而干细胞移植和细胞恢复的最新进展为恢复提供了潜在的疗法。但是，调节干细胞功能的机制仍未定义，甚至更少的是在TBI之后如何改变功能。该提案中概述的研究将检查一个分子，ephrins及其受体（EPH受体）的家族，这些家族在整个发育中的CNS中都涉及。我们最近证明，这些分子在成年茎/祖细胞，成年神经细胞和周围组织中也表达。 我们假设Ephrinb3可能 功能以阻止细胞周期并促进有丝分化后分化。 此外，在损伤后，埃菲林B3和/或其受体的过度表达可能会限制内源性茎/祖细胞增殖的能力。 我们将采用靶向基因的基因敲除小鼠来研究它们在室内区域（SVZ）内的功能。 本应用的目标1将研究其在调节SVZ中内源性成人茎/祖细胞增殖方面的功能，以及不存在ephrinb3是否可以改变细胞周期蛋白浓度。 AIM 2将采用体外测定法检查以ephrinb3的作用机理和用于调节细胞周期停滞的信号传导途径。 AIM 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及其受体的功能的基本机制信息，以调节正常和受伤的大脑中的茎/祖细胞增殖，并可能导致治疗性治疗以促进长期受伤的患者的康复。