IGF-II and Insulin Receptors in Neural Stem Cells

描述(由申请人提供)：神经前体一直以来都是发育生物学家感兴趣的。这些细胞最近引起了更广泛的神经科学界的兴趣，因为它们参与嗅觉、学习和记忆，认知能力随着年龄的增长而下降，以及它们有可能取代因脑损伤或疾病而死亡的神经元或神经胶质细胞。人们非常感兴趣的细胞是神经细胞。 干细胞(NSCs)。这些细胞自然地驻留在特定的小生境中，在那里它们接收维持它们处于原始状态所必需的信号。迄今为止，IGF-II是一种 由于IGF-II被认为是一种胎儿生长因子，干细胞利基的必要成分尚未被考虑。然而，IGF-II在脉络丛中高水平表达，脉络丛产生的脑脊液对神经干细胞来说很容易获得，因为它们将一个突起直接延伸到被脑脊液沐浴的脑室。虽然IGF-II和IGF-I都激活IGF-1R，但IGF-II也与胰岛素受体(IR-A)的剪接变体结合，支持IGF-II和IGF-I的不同作用。这一建议的总体假设是，IGF-II通过胰岛素受体对NSC的自我更新、维持和生长是必不可少的。我们的总体假设将使用可诱导的CRE驱动系进行验证，以实现IGF-II或胰岛素受体的临时离散删除。研究将在分子、细胞和行为层面上进行。识别 作为维持神经干细胞作为原始细胞所必需的IGF-II将是一项重大的科学进步。此外，确定哪些信号受体和下游转录因子被这种信号激活，可能会为放大这些重要信号的新策略提供很好的见解。 细胞促进大脑生长，在整个生命周期内保持细胞替代，并增强患病或受损大脑中的细胞替代。IGF-II在其他有成体干细胞的器官中也有表达，但在哺乳动物组织中，IGF-II在成体干细胞维持中的作用尚未被探索。因此，在完成拟议的实验后，我们将处于独特的地位，可以提交R01申请来调查这些重要和及时的问题。

DESCRIPTION (provided by applicant): Neural precursors have long been of interest to developmental biologists. These cells have recently gained the interest of the broader neuroscience community because of their involvement in olfaction, learning and memory, cognitive decline with aging and their potential to replace neurons or glial cells that have died a a consequence of brain injury or disease. The cells that are of significant interest are the neural stem cells (NSCs). These cells naturally reside within specific niches where they receive signals that are necessary to maintain them in a primitive state. To date, the possibility that IGF-II is a necessary component of the stem cell niche has not been considered largely because IGF-II has been regarded as a fetal growth factor. However, IGF-II is expressed at high levels within the choroid plexus, which produces the cerebrospinal fluid that is readily accessible to the NSCs because they extend a process directly into the ventricle that is bathed by cerebrospinal fluid. Whereas both IGF-II and IGF-I activate the IGF type 1 receptor (IGF-1R), IGF-II also binds to a splice variant isoform of the insulin receptor (IR-A) supporting distinct roles for IGF-II versus IGF-I. The overall hypothesis of this proposal is that IGF-II is essential for NSC self-renewal, maintenance and growth through the insulin receptor. Our overall hypothesis will be tested using inducible Cre driver lines to achieve both temporal discrete deletion of IGF-II or insulin receptors. Studies will be performed at the molecular, cellular and behavioral levels. Identifying IGF-II as necessary to sustain NSCs as primitive cells will be a significant scientific advance. Moreover, establishing which signaling receptor and downstream transcription factors are activated by this signal might well provide insights into new strategies to amplify these important cells to promote brain growth, maintain cell replacement across the lifespan and enhance cell replacement in the diseased or damaged brain. IGF-II is also expressed in other organs where there are adult stem cells, yet a role for IGF-II in adult stem cell maintenance has not been explored in mammalian tissues. Therefore, upon completing the proposed experiments we will be uniquely positioned to submit an R01 application to investigate these important and timely issues.