Ephrins regulate stem cell proliferation following TBI

Ephrins 调节 TBI 后干细胞增殖

• 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
• 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

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）而丧失能力，每年有50万新患者入院。TBI是一种毁灭性的残疾，可导致感觉和运动功能障碍、学习和记忆障碍以及认知缺陷。这些缺陷部分地由组织破坏和局灶性细胞损失引起。细胞替代策略是恢复脑功能的一种方法，而细胞移植的替代方法是刺激内源性神经发生。我们假设，通过提高增殖和存活率来增强神经干/祖细胞（NSPC）数量将导致组织保留和行为恢复。在急性TBI中，这可能是通过一种机制，其中NSPCs/神经母细胞为组织保护提供营养环境。我们假设ephrinB 3及其受体EphB 3和EphA 4为室管膜下区（SVZ）衍生的NSPCs提供了调节信号，限制了增殖、存活和成神经细胞迁移到损伤部位。本研究的目的1将使用转基因小鼠模型和病毒过表达方法研究ephrinB 3及其受体对皮质挫伤（CCI）损伤后NSPC增殖、存活和成神经细胞迁移的作用。目的2将检测SVZ衍生细胞在CCI损伤后恢复中的特异性，并确定抑制NSPCs中的p53是否导致增强神经发生和功能恢复。目的3将研究是否Ephs调节神经母细胞迁移通过细胞自主信号和/或通过血管重塑。总之，我们相信我们的分析将清楚地阐明SVZ在TBI后的保护作用，以及ephrinB 3及其受体是否是神经发生和TBI恢复的关键调节因子。此外，我们预计我们的研究结果将导致治疗TBI患者的治疗策略。 公共卫生关系：本提案中描述的研究将检查创伤性脑损伤后调节成人神经发生的机制，并确定刺激这一过程是否可以促进功能恢复。