Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

成人海马神经发生中的中间祖细胞

• 批准号: 7643301
• 负责人: Robert F Hevner
• 金额: $ 40.95万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643301
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Antimitotic Agents; Astrocytes; Brain; Brain region; Cell Count; Cell Proliferation; Cell division; Cells; Cellular biology; Cerebral cortex; Data; Defect; Dementia; Development; Disease; Exercise; Gene Silencing; Glutamates; Goals; Growth; Health; Hippocampus (Brain); Human; Image; Label; Lateral; Lead; Light; Mitotic; Mitotic Activity; Molecular; Monitor; Multipotent Stem Cells; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parahippocampal Gyrus; Phase; Play; Process; Production; Proliferating; Property; Public Health; Radial; Recovery; Regulation; Replacement Therapy; Role; Running; Slice; Source; Stem cells; Stroke; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Trauma; Virus; adult neurogenesis; cell motility; cell type; daughter cell; dentate gyrus; depression; design; interest; lateral ventricle; migration; nerve stem cell; nervous system disorder; nestin protein; neurogenesis; neuron loss; progenitor; relating to nervous system; retroviral transduction; stem; subventricular zone; time use; transcription factor; young adult

DESCRIPTION (provided by applicant): The overall goal of this project is to gain greater understanding of adult hippocampal neurogenesis, its mechanisms and regulation. Adult neurogenesis has important implications for designing strategies of neural replacement therapy, which could be used to treat neurodegenerative disorders and other conditions of neuronal loss. Previous studies have indicated that the adult hippocampus contains multipotent progenitors, which are the ultimate source of new neurons. However, the multipotent progenitors do not produce new neurons directly, but instead produce distinct "intermediate progenitors", which divide further to generate new neurons. The properties and dynamics of intermediate progenitors are poorly understood, due in part to a lack of specific markers. Preliminary studies for this proposal suggest that Tbr2/Eomes (hereafter referred to simply as Tbr2), a T-domain transcription factor, is specifically expressed in the intermediate progenitors. Aim 1 of this proposal is to define the cellular, molecular, and lineage properties of Tbr2+ cells, and confirm whether they correspond to intermediate progenitors. Aim 2 is to correlate changes in the number of Tbr2+ cells with regulation of neurogenesis induced by running wheel exercise and antimitotic drug treatment. Aim 3 is to define mechanisms of adult neurogenesis regulated by Tbr2 by studying mice with conditional gene inactivation. Aim 4 is to characterize the dynamics of intermediate progenitor cell division, migration, and differentiation by time-lapse imaging of hippocampal slices from normal mice, and from mice with Tbr2 inactivation. By shedding new light on the role and properties of intermediate progenitors and new neurons, this project may potentially lead to breakthroughs in adult neurogenesis and neural replacement therapy. PUBLIC HEALTH REVELANCE: Recent advances in neural stem/progenitor cell biology have raised the possibility that neurodegenerative diseases and other conditions of neuronal loss, such as trauma and stroke, could be treated by neural replacement therapy. This project will study adult hippocampal intermediate progenitor cells, a special type of neural progenitors that produce glutamatergic neurons, similar to those that are depleted in Alzheimer dementia and other diseases that affect the cerebral cortex.

描述(申请人提供)：这个项目的总体目标是更好地了解成人海马神经发生，其机制和调节。成人神经发生对设计神经替代治疗策略具有重要意义，可用于治疗神经退行性疾病和其他神经元丧失的情况。先前的研究表明，成年海马区含有多能前体细胞，它们是新神经元的最终来源。然而，多能前体细胞并不直接产生新的神经元，而是产生不同的“中间前体细胞”，这些中间前体细胞进一步分裂产生新的神经元。人们对中间前体细胞的性质和动态知之甚少，部分原因是缺乏特定的标记。对这一建议的初步研究表明，Tbr2/Eome(以下简称Tbr2)是一种T结构域转录因子，在中间前体细胞中特异表达。这项建议的目的1是定义Tbr2+细胞的细胞、分子和谱系特性，并确认它们是否与中间前体细胞相对应。目的2研究Tbr2+细胞数量的变化与跑轮运动和抗有丝分裂药物治疗诱导的神经发生调控之间的关系。目的3通过对条件性基因失活小鼠的研究，明确Tbr2对成体神经发生的调控机制。目的4通过对正常小鼠和Tbr2失活小鼠的海马片进行时间推移成像，研究中间祖细胞分裂、迁移和分化的动力学特征。通过揭示中间前体细胞和新神经元的作用和特性，该项目可能会在成人神经发生和神经替代治疗方面取得突破。 公共卫生评论：神经干细胞/祖细胞生物学的最新进展提高了神经退行性疾病和其他神经元丧失的情况，如创伤和中风，可以通过神经替代疗法治疗的可能性。该项目将研究成人海马区的中间前体细胞，这是一种特殊类型的神经前体细胞，可以产生谷氨酸能神经元，类似于阿尔茨海默病和其他影响大脑皮层的疾病中耗尽的那些细胞。