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A non-secreted form of IGF-1 is a protective factor for neural stem cells

非分泌形式的 IGF-1 是神经干细胞的保护因子

基本信息

批准号：
8307841
负责人：
ANTHONY John WINDEBANK
金额：
$ 35.51万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Loss of brain function is arguably the most dreaded consequence of getting old. We propose to test the hypothesis that restoration of youthful levels of mechano growth factor (MGF) will arrest the decline in adult neurogenesis that is linked to loss of brain function in old individuals. We will take advantage of an inducible gene expression system that utilizes control elements from the lac operon of E. coli to induce or repress transgene expression in the mouse. We will ask two questions: 1) if we induce transgenic MGF expression before endogenous MGF levels have started to decline in the mouse, can we prevent neuronal attrition in areas supplied by adult neurogenesis? And, 2) if we induce MGF when neurogenesis is already moderately or severely impaired, can we arrest neuronal attrition so that no further damage takes place or even repair the damage done up to that point? Mechano growth factor (MGF) is a non-hormonal form of insulin-like growth factor-1 (IGF-1), one of the most important postnatal hormones controlling growth in mammals. Like IGF-1, which peaks in adolescence when growth peaks and declines to low levels in old individuals, MGF is expressed in juvenile tissue at a much higher level than in tissue from old animals. MGF was discovered in adult muscle stem cells as a factor that stimulates proliferation after muscle stretch, stress, or damage. We have discovered that mechano growth factor is also expressed in adult neural stem cells (NSCs), where we think it might play a similar role. We propose that MGF is a critical juvenile protective factor that maintains brain function throughout life by stimulating the production of new neurons to replace those that have worn-out, become damaged, or died. The link between MGF, which is a non-secreted form of IGF-1, and the ability of stem cells to proliferate sheds new light on how the insulin/IGF system might regulate aging and longevity. Previous studies have shown very clearly that changes in the level of the insulin/IGF receptor and/or the activity of its associated signal transduction cascade can shorten or lengthen lifespan in a number of experimental animal species. Because MGF is not a hormone, but an isoform of IGF-1 that remains in the cell in which it is synthesized, it can have direct effects on cellular events that are independent of insulin/IGF signaling. In stem cells, the effect of insulin/IGF system on proliferation could be a combination of MGF intracellular activities and the activities of the signaling pathway. This could be one way the stem cell theory of aging and the known effects of the insulin/IGF-1 system on lifespan intersect. Loss of brain function is arguably the most dreaded consequence of getting old. We propose to test the hypothesis that restoration of youthful levels of mechano growth factor (MGF), a non-hormonal form of insulin-like growth factor (IGF)-1, will arrest the decline in adult neurogenesis that is linked to loss of brain function in old individuals. We will test this hypothesis in vivo, taking advantage of an inducible expression system our lab has developed that will allow us to flip the expression of MGF on and off at will.

描述（由申请人提供）：大脑功能的丧失可以说是变老最可怕的后果。我们建议测试的假设，恢复年轻水平的机械生长因子（MGF）将逮捕成年神经发生的下降，这是与老年人的脑功能丧失。我们将利用一个可诱导的基因表达系统，该系统利用来自大肠杆菌乳糖操纵子的控制元件。coli中诱导或抑制小鼠中的转基因表达。我们会问两个问题：1）如果我们在小鼠内源性MGF水平开始下降之前诱导转基因MGF表达，我们能否防止由成人神经发生提供的区域中的神经元磨损？2）如果我们在神经发生已经中度或重度受损时诱导MGF，我们是否可以阻止神经元的磨损，使其不再发生进一步的损伤，甚至修复到那时为止所造成的损伤？机械生长因子（MGF）是胰岛素样生长因子-1（IGF-1）的非激素形式，IGF-1是控制哺乳动物生长的最重要的产后激素之一。与IGF-1一样，IGF-1在青春期达到峰值，此时生长达到峰值，并在老年个体中下降至低水平，MGF在幼年组织中的表达水平远远高于老年动物的组织。MGF在成人肌肉干细胞中被发现是一种在肌肉拉伸，压力或损伤后刺激增殖的因子。我们已经发现，机械生长因子也在成体神经干细胞（NSCs）中表达，我们认为它可能在其中发挥类似的作用。我们认为MGF是一种关键的青少年保护因子，通过刺激新神经元的产生来取代那些已经磨损，受损或死亡的神经元，从而在整个生命过程中维持大脑功能。MGF是IGF-1的非分泌形式，与干细胞增殖能力之间的联系为胰岛素/IGF系统如何调节衰老和长寿提供了新的线索。以前的研究已经非常清楚地表明，胰岛素/IGF受体水平和/或其相关信号转导级联反应活性的变化可以缩短或延长许多实验动物物种的寿命。因为MGF不是一种激素，而是IGF-1的一种亚型，它保留在合成它的细胞中，它可以对独立于胰岛素/IGF信号传导的细胞事件产生直接影响。在干细胞中，胰岛素/IGF系统对增殖的影响可能是MGF细胞内活性和信号通路活性的组合。这可能是衰老的干细胞理论和胰岛素/IGF-1系统对寿命的已知影响交叉的一种方式。大脑功能的丧失可以说是变老最可怕的后果。我们建议测试这一假设，即恢复年轻水平的机械生长因子（MGF），胰岛素样生长因子（IGF）-1的非激素形式，将阻止与老年人脑功能丧失有关的成年神经发生的下降。我们将在体内测试这一假设，利用我们实验室开发的诱导表达系统，使我们能够随意打开和关闭MGF的表达。