Ephrins regulate stem cell proliferation following TBI

Ephrins 调节 TBI 后干细胞增殖

• 批准号: 8792874
• 负责人: Daniel Jon Liebl
• 金额: $ 33.47万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792874
• 关键词: Ablation; Acute; Address; Affect; American; Apoptotic; Attenuated; Behavioral; Blood Vessels; Brain; Cell Count; Cell Proliferation; Cells; Cognitive deficits; Cortical Contusions; Defect; Development; Environment; Eph Family Receptors; EphA4 Receptor; EphB3 Receptor; Ephrins; Family member; Foundations; Ganciclovir; Gene Targeting; Grant; Health; Immigration; Individual; Injury; Knock-out; Laboratories; Lead; Learning; Mediator of activation protein; Memory impairment; Modeling; Mus; Mutant Strains Mice; Nature; Operative Surgical Procedures; Outcome; Paralysed; Patients; Phase I Clinical Trials; Play; Population; Postdoctoral Fellow; Process; Recovery; Recovery of Function; Role; Sensory; Signal Transduction; Site; Solid; Specificity; Stem cells; Stream; Technology; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Traumatic Brain Injury; Traumatic Brain Injury recovery; Traumatic CNS injury; Tumor Angiogenesis; United States; Vascular remodeling; Viral; adult neurogenesis; cell injury; controlled cortical impact; design; disability; experience; functional improvement; gain of function; improved; injured; loss of function; migration; motor disorder; mouse model; nestin protein; neuroblast; neurogenesis; neuromechanism; neurotransmission; novel strategies; novel therapeutics; receptor; relating to nervous system; repaired; stem; subventricular zone

DESCRIPTION (provided by applicant): Seven million Americans are presently incapacitated as a result of traumatic brain injury (TBI) with 500,000 new patients admitted each year. TBI is a devastating disability that leads to sensory and motor dysfunction, learning and memory impairment, and cognitive deficits. These defects result from, in part, tissue destruction and focal cell losses. Cell replacement strategies have been one approach to restoring brain function, and an alternative to cellular transplantation is stimulation of endogenous neurogenesis. We hypothesize that enhancement of neural stem/progenitor cell (NSPC) numbers through improved proliferation and survival will lead to tissue sparing and behavioral recovery. In acute TBI, this is likely through a mechanism where NSPCs/neuroblasts provide a trophic environment for tissue sparing. We hypothesize that ephrinB3 and its receptors, EphB3 and EphA4, provide a regulatory signal to subventricular zone (SVZ)-derived NSPCs, which limit proliferation, survival, and neuroblast migration to the site of injury. Aim 1 of this grant will examine the role of ephrinB3 and its receptors on NSPC proliferation, survival, and neuroblast migration following cortical contusion impact (CCI) injury using transgenic mouse models and viral over-expression approaches. Aim 2 will examine the specificity of SVZ-derived cells in recovery following CCI injury, and determine whether inhibiting p53 in NSPCs leads to enhance neurogenesis and functional recovery. Aim 3 will examine whether Ephs regulate neuroblast migration through cell autonomous signaling and/or through vascular remodeling. Together, we believe our analysis will clearly address the protective role of the SVZ after TBI, and whether ephrinB3 and its receptors are critical regulators of neurogenesis and TBI recovery. Furthermore, we anticipate our findings will lead to therapeutic strategies to treat TBI patients.

描述(申请人提供)：目前有700万美国人因创伤性脑损伤(TBI)而丧失工作能力，每年有500,000名新患者入院。脑外伤是一种毁灭性的残疾，会导致感觉和运动功能障碍、学习和记忆障碍以及认知障碍。这些缺陷的部分原因是组织破坏和局灶性细胞丢失。细胞替代策略一直是恢复大脑功能的一种方法，而细胞移植的另一种选择是刺激内源性神经发生。我们假设，通过改善增殖和存活来增加神经干细胞/祖细胞(NSPC)的数量将导致组织保留和行为恢复。在急性脑损伤中，这可能是通过NSPC/神经母细胞为组织保留提供营养环境的机制来实现的。我们假设ewitinB3及其受体EphB3和EphA4向脑室下区(SVZ)来源的NSPC提供调节信号，限制NSPC的增殖、存活和神经母细胞向损伤部位的迁移。这项拨款的目的1将通过转基因小鼠模型和病毒过度表达方法，研究ewitinB3及其受体在皮质挫伤(CCI)损伤后NSPC增殖、存活和神经母细胞迁移中的作用。目的2检测SVZ来源的细胞在CCI损伤后恢复过程中的特异性，并确定抑制NSPC中的P53是否能促进神经发生和功能恢复。目的3将研究Ephs是否通过细胞自主信号和/或血管重塑来调节神经母细胞的迁移。总之，我们相信，我们的分析将清楚地解决脑损伤后SVZ的保护作用，以及ewitinB3及其受体是否是神经发生和脑损伤恢复的关键调节因子。此外，我们预计我们的发现将导致治疗脑损伤患者的治疗策略。

项目成果

Traumatic brain injury-induced hippocampal neurogenesis requires activation of early nestin-expressing progenitors.

创伤性脑损伤引起的海马神经发生需要激活早期表达巢穴的祖细胞。

• DOI: 10.1523/jneurosci.4629-08.2008
• 发表时间: 2008-11-26
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Yu TS;Zhang G;Liebl DJ;Kernie SG
• 通讯作者: Kernie SG