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

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。我们建议测试一个假设，即恢复年轻时的机械生长因子（MGF）水平将阻止与老年人脑功能丧失有关的成人神经发生的下降。我们将利用一个可诱导的基因表达系统，该系统利用大肠杆菌lac操纵子的控制元件来诱导或抑制小鼠的转基因表达。我们将提出两个问题：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，我们能否防止成年神经发生供应区域的神经元磨损？2)如果我们在神经发生已经中度或严重受损的情况下诱导MGF，我们能否阻止神经元的消耗，从而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（Mechano growth factor， MGF）是胰岛素样生长因子-1 （IGF-1）的一种非激素形式，是哺乳动物控制生长的最重要的产后激素之一。就像IGF-1一样，IGF-1在青春期生长高峰时达到峰值，在老年个体中下降到较低水平，MGF在幼年动物组织中的表达水平远高于老年动物组织。MGF是在成体肌肉干细胞中发现的一种刺激肌肉拉伸、应激或损伤后增殖的因子。我们发现机械生长因子也在成体神经干细胞（NSCs）中表达，我们认为它可能在那里发挥类似的作用。我们认为MGF是一种关键的幼年保护因子，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，从而维持大脑在整个生命中的功能。MGF是IGF-1的一种非分泌形式，它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寿命提供了新的线索。先前的研究已经非常清楚地表明，在许多实验动物中，胰岛素/IGF受体水平和/或相关信号转导级联活性的变化可以缩短或延长寿命。由于MGF不是一种激素，而是IGF-1的一种同型，它保留在合成它的细胞中，因此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结合。这可能是干细胞衰老理论和胰岛素/IGF-1系统对寿命的已知影响的一种交叉方式。大脑功能的丧失可以说是变老最可怕的后果。我们建议测试一个假设，即恢复年轻时的机械生长因子（MGF）水平，一种非激素形式的胰岛素样生长因子(IGF)-1，将阻止与老年人脑功能丧失相关的成人神经发生的下降。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。

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.