IGF-II and Insulin Receptors in Neural Stem Cells

神经干细胞中的 IGF-II 和胰岛素受体

• 批准号: 8734489
• 负责人: STEVEN W LEVISON
• 金额: $ 23.61万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734489
• 关键词: 1 year old; Adoption; Adult; Affect; Age; Aging; Alternative Splicing; Antibodies; Bathing; Behavioral; Binding; Birth; Blood; Blood Circulation; Brain; Brain Diseases; Brain Injuries; Caenorhabditis elegans; Cell Maintenance; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Color; Communities; Data; Development; Drosophila genus; Embryonic Development; Epidemiology; Failure; Fetal Growth; Flow Cytometry; Goals; Growth; Growth Factor; Hippocampus (Brain); Homeostasis; Human; Hybrids; Impaired cognition; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Knowledge; Label; Lead; Learning; Life; Longevity; Maintenance; Memory; Methods; Molecular; Mus; Mutant Strains Mice; Neuroglia; Neurons; Neurosciences; Organ; Parahippocampal Gyrus; Physiological; Population; Positioning Attribute; Process; Production; Protein Isoforms; Publishing; RNA Splicing; Receptor Signaling; Role; Scientific Advances and Accomplishments; Sensory; Signal Transduction; Smell Perception; Stem cells; Stromal Cells; Structure of choroid plexus; System; Testing; Thymidine; Tissues; Variant; activating transcription factor; adult stem cell; age related; aging brain; analog; behavioral deficiency; cognitive function; dentate gyrus; fetal; injured; insight; insulin signaling; interest; mouse model; mutant; nerve stem cell; neurogenesis; novel; novel therapeutics; olfactory bulb; postnatal; primitive cell; progenitor; public health relevance; pup; receptor; reconstitution; repaired; research study; self-renewal; stem cell niche; stem cell therapy; stemness

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.

描述（由申请人提供）：神经前体细胞长期以来一直受到发育生物学家的关注。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、随着衰老而导致的认知能力下降，以及它们替代因脑损伤或疾病而死亡的神经元或神经胶质细胞的潜力。最令人感兴趣的细胞是神经细胞 干细胞（NSC）。这些细胞自然地存在于特定的生态位中，在那里它们接收维持其原始状态所必需的信号。迄今为止，IGF-II 的可能性 干细胞生态位的必要组成部分尚未被广泛考虑，因为 IGF-II 已被视为胎儿生长因子。然而，IGF-II 在脉络丛内高水平表达，脉络丛产生脑脊液，NSC 很容易接触到脑脊液，因为它们将一个过程直接延伸到被脑脊液沐浴的心室。虽然 IGF-II 和 IGF-I 均激活 IGF 1 型受体 (IGF-1R)，但 IGF-II 还与胰岛素受体 (IR-A) 的剪接变体亚型结合，支持 IGF-II 与 IGF-I 的不同作用。我。该提议的总体假设是 IGF-II 对于 NSC 通过胰岛素受体的自我更新、维持和生长至关重要。我们的总体假设将使用诱导型 Cre 驱动系进行测试，以实现 IGF-II 或胰岛素受体的时间离散删除。研究将在分子、细胞和行为水平上进行。 识别 IGF-II 作为维持 NSC 作为原始细胞所必需的，将是一项重大的科学进步。此外，确定该信号激活哪些信号受体和下游转录因子很可能为放大这些重要信号的新策略提供见解。 细胞促进大脑生长，在整个生命周期内维持细胞更新，并增强患病或受损大脑的细胞更新。 IGF-II 也在存在成体干细胞的其他器官中表达，但 IGF-II 在成体干细胞维持中的作用尚未在哺乳动物组织中进行探索。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且及时的问题。