Aging and Neurogenesis

衰老与神经发生

• 批准号: 6899743
• 负责人: Kunlin Jin
• 金额: $ 45.04万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899743
• 关键词: age difference; aging; animal old age; behavior test; brain mapping; bromodeoxyuridine; cell differentiation; cell migration; cell proliferation; cerebral ischemia /hypoxia; dentate gyrus; histology; immunocytochemistry; laboratory rat; mature animal; nerve stem cell; neurogenesis; neuropharmacology; neurotrophic factors; stroke; voltage /patch clamp

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.

描述（由申请人提供）：衰老与中风和神经退行性疾病发病率的显着增加有关，这些是美国 70 岁及以上老年人残疾的主要原因。尽管在了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，但广泛有效的治疗方法仍然难以实现。成人大脑（包括老年大脑）的海马齿状回头侧室下区（SVZ）和颗粒下区（SGZ）的神经发生在整个生命过程中持续发生，为人类干细胞治疗带来了令人兴奋的新前景。然而，新生神经细胞的神经发生能力和命运在老年大脑中是否保持不变或发生变化，以及产生的神经元是否真正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衰老大脑中内源干细胞/祖细胞的生物学特性，并更深入地了解细胞疗法治疗缺血性中风和神经退行性疾病等与年龄相关的疾病的潜力。 将实现以下具体目标： 1. 探讨局灶性脑缺血后老年大鼠与青壮年和中年大鼠相比，内源性神经发生是否增加、减少或不变，并确定体内局灶性脑缺血后神经发生的区域和时间特征。 2.确定青、中、老年大鼠大脑缺血后海马齿状回SVZ和SGZ新生神经干/祖细胞的去向。 3. 确定与年轻成年和中年大鼠大脑相比，施用相同或不同的神经发生因子是否会促进老年大鼠大脑的神经发生，并改善体内局灶性脑缺血后的功能结果。 4. 确定在体内局灶性脑缺血后，从SVZ和SGZ迁移的神经元细胞是否发育出成熟的表型神经元特征并表现出青壮年、中年和老年大鼠脑中神经元的功能特性。