Aging and Neurogenesis

描述（由申请人提供）：虽然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在成年人大脑中进行的。因此，更好地了解如何神经干/祖细胞（NSC）在老年脑卒中后的调节似乎是必要的。在过去的资助期间，我们研究了衰老在中风后神经发生中的作用。我们在下一个资助期的研究目标是关注衰老对中风诱导的神经发生的潜在调节机制。具体来说，我们将探讨Notch通路在衰老过程中神经发生中的作用。已有研究表明Notch信号通路在神经干细胞的维持、增殖和分化过程中起重要作用。最近的证据表明，Notch 1信号在成人神经发生的调节中是保守的。我们的初步研究表明，Notch 1及其下游靶点在SVZ细胞中表达，并且在抑制或激活Notch 1通路后，正常成人SVZ中BrdU阳性（增殖）细胞的数量显著改变。此外，我们发现，Notch 1信号在SVZ激活中风后，中风诱导的细胞增殖的SVZ可以通过抑制Notch 1通路在成年人的大脑。这些结果导致我们的假设，Notch 1信号是必不可少的神经发生在成年人的大脑和Notch 1信号活性的变化可能会直接或间接地导致神经发生的年龄依赖性下降，包括中风后。为了验证这一假设，我们提出：（1）检测衰老对SVZ中Notch 1信号分子表达的时间分布，并表征成年与老年大鼠脑中表达Notch 1通路分子的SVZ细胞的表型;（2）探讨Notch 1信号通路改变对年轻人SVZ细胞增殖及其他信号通路的影响。成年和老年大鼠脑中的神经发生;（3）检测中风后成年和老年大鼠脑SVZ中Notch 1通路的活性;（4）评估Notch 1通路的强制激活或阻断对中风后成年和老年大鼠脑SVZ中神经发生的影响。 所提出的实验的长期目标是，通过研究调节老年脑中中风诱导的神经发生的机制，以更好地理解在正常衰老和与年龄相关的神经疾病如中风中控制神经发生的基本原理。

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.