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Ephrins regulate stem cell proliferation following TBI

Ephrins 调节 TBI 后干细胞增殖

基本信息

批准号：
8105912
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
项目类别：
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/8105912
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 Functional disorder Ganciclovir Gene Targeting Grant Immigration Individual Injury Knock-out Laboratories Lead Learning Mediator of activation protein Memory impairment Modeling Motor 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 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 mouse model nestin protein neuroblast neurogenesis neuromechanism novel strategies novel therapeutics receptor relating to nervous system repaired stem subventricular zone

项目摘要

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. PUBLIC HEALTH RELEVANCE: The studies described in this proposal will examine the mechanisms that regulate adult neurogenesis following traumatic brain injury, and determine whether stimulating of this process can function to promote functional recovery.

描述（由申请人提供）：目前有700万美国人因创伤性脑损伤（TBI）而丧失行为能力，每年有50万新患者入院。创伤性脑损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缺陷。这些缺陷部分是由组织破坏和局灶细胞损失造成的。细胞替代策略是恢复脑功能的一种方法，而细胞移植的另一种选择是刺激内源性神经发生。我们假设通过提高增殖和存活来增强神经干/祖细胞（NSPC）的数量将导致组织保留和行为恢复。在急性TBI中，这可能是通过NSPCs/神经母细胞为组织保留提供营养环境的机制实现的。我们假设ephrinB3及其受体EphB3和EphA4向室下区（SVZ）衍生的NSPCs提供调节信号，从而限制增殖、存活和神经母细胞向损伤部位的迁移。该资助的目的1将使用转基因小鼠模型和病毒过表达方法研究ephrinB3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将检验svz来源的细胞在CCI损伤后恢复中的特异性，并确定抑制NSPCs中的p53是否会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传导和/或血管重塑调节神经母细胞迁移。总之，我们相信我们的分析将清楚地说明脑外伤后SVZ的保护作用，以及ephrinB3及其受体是否是神经发生和脑外伤恢复的关键调节因子。此外，我们预计我们的发现将为治疗TBI患者提供治疗策略。