Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

描述（由申请人提供）：该项目的总体目标是更深入地了解成人海马神经发生及其机制和调控。成人神经发生对于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疾病。先前的研究表明，成人海马含有多能祖细胞，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”，这些中间祖细胞进一步分裂产生新的神经元。由于缺乏特定的标记物，人们对中间祖细胞的性质和动态知之甚少。初步研究表明，Tbr2/Eomes（以下简称Tbr2）是一种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是确定Tbr2+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的调节联系起来。目的3：通过研究条件性基因失活小鼠，明确Tbr2调控成人神经发生的机制。目的4是通过对正常小鼠和Tbr2失活小鼠的海马切片进行延时成像，表征中间祖细胞分裂、迁移和分化的动力学。通过揭示中间祖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。

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.