Aging and Neurogenesis

衰老与神经发生

• 批准号: 8508771
• 负责人: Kunlin Jin
• 金额: $ 27万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508771
• 关键词: Address; Adult; Aging; Animals; Brain; Brain region; Bromodeoxyuridine; Cell Count; Cell Fate Control; Cell Proliferation; Cells; Exhibits; Funding; Goals; Hippocampus (Brain); In Vitro; Maintenance; Neurons; Newborn Infant; Notch Signaling Pathway; Pathway interactions; Phenotype; Pilot Projects; Play; Population; Process; Proliferating; Property; Rattus; Regulation; Research; Rodent; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; Stroke; Testing; Vascular Endothelial Growth Factors; adult neurogenesis; age related; aged; aging brain; cell type; dentate gyrus; in vivo; migration; nervous system disorder; neurogenesis; neurotrophic factor; normal aging; notch protein; postnatal; public health relevance; receptor; relating to nervous system; research study; response; stem; subventricular zone; young adult

DESCRIPTION (provided by applicant): Although stroke occurs mainly in the aged population, most animal studies investigating both stroke and neurogenesis are conducted on young-adult brains. Hence, better understanding of how neural stem/progenitor cells (NSCs) are regulated after stroke in the aged brain seems essential. In the past funding period, we study the roles of aging in neurogenesis after stroke. The goal of our research in the next funding period is to focus on the mechanisms underlying regulation of stroke-induced neurogenesis by aging. Specifically, we will explore the role of the Notch pathway in neurogenesis during aging. Previous studies show that Notch signaling pathway plays critical roles during maintenance, proliferation, and differentiation of NSCs in developing brain. Recent evidence shows that Notch1 signaling is conserved in the regulation of adult neurogenesis. Our pilot studies show that Notch1 and its downstream targets are expressed in SVZ cells, and that the number of BrdU-positive (proliferating) cells in the normal adult SVZ is significantly altered after inhibiting or activating the Notch1 pathway. In addition, we find that Notch1 signaling in the SVZ is activated after stroke and that stroke-induced cell proliferation in the SVZ can be blocked by inhibiting the Notch1 pathway in young-adult brain. These results led to our hypothesis that Notch1 signaling is essential for neurogenesis to occur in the adult brain and that changes in Notch1 signaling activity may contribute, directly or indirectly, to the aged-dependent decline in neurogenesis, including that following stroke. To test this hypothesis, we propose to: (1) to examine the temporal profiles of Notch1 signaling molecule expression in the SVZ in response to aging, and to characterize the phenotypes of SVZ cells expressing Notch1 pathway molecules in the young-adult vs. aged rat brain; (2) to investigate the effect of altering the Notch1 pathway on cell proliferation and other signaling pathways in the SVZ of young-adult and aged rat brain in vivo; (3) to examine Notch1 pathway activity in the SVZ of the young-adult and aged rat brain after stroke; (4) to assess the effect of forced activation or blockade of the Notch1 pathway on neurogenesis in SVZ of young-adult and aged rat brain after stroke in vivo. The long-term goal of the proposed experiments is, by studying the mechanisms that regulate stroke- induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke.

描述（由申请人提供）：尽管中风主要发生在老年人群中，但大多数研究中风和神经发生的动物研究都是对年轻成年大脑进行的。因此，对衰老大脑中风后如何调节神经干/祖细胞（NSC）的更好理解似乎是必不可少的。在过去的资金期间，我们研究了中风后衰老在神经发生中的作用。在下一个资金期间，我们研究的目的是关注通过衰老对中风引起的神经发生的基本机制。具体而言，我们将探讨Notch途径在衰老过程中的神经发生中的作用。先前的研究表明，Notch信号通路在发育中NSC的维持，增殖和分化过程中起着关键作用。最近的证据表明，Notch1信号在成人神经发生的调节中保守。我们的试点研究表明，Notch1及其下游靶标在SVZ细胞中表达，并且在正常成年SVZ中的BRDU阳性（增殖）细胞的数量在抑制或激活NotCH1途径后会显着改变。此外，我们发现中风后SVZ中的Notch1信号传导被激活，并且可以通过抑制年轻成人大脑中的Notch1途径来阻断中风诱导的SVZ中的细胞增殖。这些结果导致了我们的假设：Notch1信号对于神经发生在成年大脑中是必不可少的，而Notch1信号传导活性的变化可能直接或间接地导致神经发生的老化依赖性下降，包括中风后。为了检验这一假设，我们建议：（1）检查SVZ中Notch1信号分子在响应衰老的情况下的时间谱，并表征表达notch1途径分子的SVZ细胞的表型； （2）研究改变Notch1途径对体内年轻人和老年大鼠脑SVZ细胞增殖和其他信号通路的影响； （3）检查中风后年轻成年和老年大脑的SVZ中的Notch1途径活性； （4）评估体内卒中后，notch1途径强制激活或阻断Notch1途径对年轻成年和老年大鼠脑的神经发生的影响。 提出的实验的长期目标是，通过研究调节衰老大脑中风诱导神经发生的机制，以更好地理解对正常衰老和年龄相关的神经系统疾病（如中风）的神经发生的基本原理。