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）：神经前体一直是发育生物学家的兴趣。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，随着年龄的增长认知能力下降，以及它们取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。重要的细胞是神经细胞， 干细胞（NSC）。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。到目前为止，IGF-II是一种 由于IGF-II被认为是一种胎儿生长因子，因此，干细胞龛的必要成分在很大程度上没有得到考虑。然而，IGF-II在脉络丛内以高水平表达，脉络丛产生容易接近NSC的脑脊液，因为它们将过程直接延伸到被脑脊液浸泡的脑室中。尽管IGF-II和IGF-I均激活IGF 1型受体（IGF-1 R），但IGF-II还结合胰岛素受体（IR-A）的剪接变体同种型，支持IGF-II与IGF-I的不同作用。该建议的总体假设是IGF-II通过胰岛素受体对NSC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缺失。研究将在分子、细胞和行为水平上进行。 识别 IGF-II作为维持神经干细胞作为原始细胞所必需的将是一个重大的科学进步。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的信号的新策略提供见解。 细胞促进大脑生长，在整个生命周期中保持细胞替换，并增强患病或受损大脑中的细胞替换。IGF-II也表达于存在成体干细胞的其他器官中，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探索。因此，在完成拟议的实验后，我们将处于独特的地位，提交R 01申请，以调查这些重要而及时的问题。