Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

描述（由申请人提供）：本项目的总体目标是获得对成人海马神经发生，其机制和调节的更深入的了解。成人神经发生对设计神经替代疗法的策略具有重要意义，该疗法可用于治疗神经退行性疾病和其他神经元丢失的病症。先前的研究表明，成年海马含有多能祖细胞，它们是新神经元的最终来源。然而，多能祖细胞不直接产生新的神经元，而是产生不同的“中间祖细胞”，其进一步分裂以产生新的神经元。中间祖细胞的性质和动力学知之甚少，部分原因是缺乏特异性标记。初步研究表明，Tbr 2/Eomes（以下简称Tbr 2），一个T-结构域转录因子，在中间祖细胞中特异性表达。本提案的目的1是定义Tbr 2+细胞的细胞、分子和谱系特性，并确认它们是否对应于中间祖细胞。目的2是将Tbr 2+细胞数量的变化与转轮运动和抗有丝分裂药物治疗诱导的神经发生调节相关。目的3通过对条件性基因失活小鼠的研究，阐明Tbr 2调控成年神经发生的机制。目的4是通过正常小鼠和Tbr 2失活小鼠海马切片的延时成像来表征中间祖细胞分裂、迁移和分化的动态。通过对中间祖细胞和新神经元的作用和性质的新认识，该项目可能会导致成人神经发生和神经替代治疗的突破。 公共卫生部门：神经干/祖细胞生物学的最新进展已经提高了神经退行性疾病和其他神经元损失状况（如创伤和中风）可以通过神经替代疗法治疗的可能性。该项目将研究成年海马中间祖细胞，这是一种特殊类型的神经祖细胞，可产生海马能神经元，类似于阿尔茨海默氏症和其他影响大脑皮层的疾病中耗尽的神经元。

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.