Aging and Neurogenesis

描述（由申请人提供）：老龄化与中风和神经退行性疾病的发病率显著增加相关，这是美国70岁及以上人群残疾的主要原因。尽管在理解这些疾病中神经元细胞死亡的分子机制方面取得了进展，但广泛有效的治疗仍然难以实现。通过观察到神经发生在成人脑（包括老年脑）中海马齿状回的头侧脑室下区（SVZ）和颗粒下区（SGZ）中持续发生，已经提出了人类干细胞治疗的令人兴奋的新前景。然而，神经发生的能力和新生神经细胞的命运是否在老年大脑中保持不变或发生变化，以及产生的神经元是否真的有助于脑损伤后老年大脑的功能恢复尚不清楚。这些问题的澄清将使我们更好地了解内源性干/祖细胞在老年脑的生物学和更深入地了解细胞治疗的潜力与年龄相关的疾病，如缺血性中风和神经退行性疾病。 将处理以下具体目标： 1.探讨老年大鼠局灶性脑缺血后内源性神经发生与青年和中年大鼠相比是否增加、减少或不变，并在体内确定局灶性脑缺血后神经发生的区域和时间分布。 2.确定青年、中年和老年大鼠脑缺血后海马齿状回SVZ和SGZ新生神经干/祖细胞的去向。 3.确定给予相同或不同的神经发生因子是否促进老年大鼠与年轻成年大鼠和中年大鼠脑中的神经发生，并改善体内局灶性脑缺血后的功能结果。 4.确定从SVZ和SGZ迁移的神经元细胞在体内局灶性脑缺血后是否发育成熟的表型神经元特征并表现出年轻成年、中年和老年大鼠脑中神经元的功能特性。

DESCRIPTION (provided by applicant): Aging is associated with a striking increase in the incidence of stroke and neurodegenerative diseases, which are major causes of disability among those aged 70 years and older in the United States. Despite progress in understanding molecular mechanisms of neuronal cell death in these diseases, widely effective treatment remains elusive. Exciting new prospects for human stem cell therapy have been raised by the observation that neurogenesis continues to occur throughout life in the rostral subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus in the adult brain, including aged brain. However, whether the capacity for neurogenesis and the fate of newborn neural cells remain the same or change in aged brain, and whether the neurons produced actually contribute to functional recovery of the aged brain after cerebral injury are unclear. Clarification of these issues will give us a better understanding of the biology of endogenous stem/progenitor cells in aged brain and more insight into the potential of cell therapy for age-related diseases such as ischemic stroke and neurodegenerative disorders. The following specific aims will be addressed: 1. Explore whether endogenous neurogenesis is increased, decreased or unchanged in aged compared to young adult and middle-aged rats after focal cerebral ischemia and determine the regional and temporal profiles of neurogenesis after focal cerebral ischemia in vivo. 2. Determine the destinations of newly generated neural stem/progenitor cells from SVZ and SGZ of the hippocampal dentate gyrus in young adult, middle-aged and aged rat brain after ischemia. 3. Establish whether administration of the same or different neurogenesis factors promotes neurogenesis in aged compared to young adult and middle-aged rat brain and improves functional outcome after focal cerebral ischemia in vivo. 4. Determine whether neuronal cells that migrate from SVZ and SGZ develop mature phenotypic neuronal features and exhibit functional properties of neurons in young adult, middle-aged and aged rat brain after focal cerebral ischemia in vivo.