Essential Function of miR-29 in the Mature Brain

项目摘要(30行文本) 神经元生物学被低估的一个方面是，作为有丝分裂后分化的神经元 成熟后，它们会经历动态变化，以确保成熟的神经系统能够长期- 长期生存和功能。了解这些机制对于人类长期内稳态至关重要 成年人的大脑很重要，因为他们的功能障碍会增加神经元对年龄相关的脆弱性 神经退行性变。 我们已经鉴定miR-29是一种微小RNA，随着神经元的成熟而显著诱导。和平号29是 在胚胎发育过程中检测不到，但其水平在2个月内诱导300倍以上， 在成人大脑中，6个月后甚至更大。与保持较高的miR-29水平相比 在阿尔茨海默病患者中，正常成人大脑中miR-29水平显著降低。和平号29是 被认为以AD通路中的许多基因为靶点，包括BACE1、ADAM10、PICALM和NAV3。 为了评估miR-29的功能重要性，我们最近培育了miR-29可以被 有条件地删除。在全身或大脑中缺乏miR-29的小鼠出生时都是正常的，但 然后逐渐下降，表现出神经缺陷和早期死亡。这些结果表明，miR-29 在成熟的大脑中起着至关重要的作用。我们的假设是miR-29，虽然胚胎不需要 发育，对维持成人大脑的长期内稳态具有重要的生理学意义。 因此，miR-29水平的降低可能会增加成熟神经元成为 在阿尔茨海默病的背景下出现功能障碍。 我们建议的总体重点是了解维持非常高的 在正常大脑中miR-29的水平，以批判性地检查miR-29在成人大脑中的功能，并 评价miR-29治疗阿尔茨海默病的潜力。具体地说，在目标1中，我们将测试 假设成熟神经元miR-29转录增加是染色质去抑制的结果。 重要的是，我们还将审查MIR-29的大幅增加是否是由于 成熟神经元的加工和稳定性。在目标2中，我们将重点定义分子、细胞和 删除成人大脑中miR-29的行为后果。评价miR-1的治疗潜力 29对于阿尔茨海默病，我们也产生了miR-29可以有条件地过表达的小鼠。 因此，在目标3中，我们将检查miR-29的过表达是否有利于突变的APP敲入 阿尔茨海默病小鼠模型。 总体而言，我们很高兴能研究一种名为miR-29的分子，它在 成熟的大脑。我们的研究将有助于确定其作用机制，并评估其治疗效果。 在阿尔茨海默氏症背景下的潜力。

Project Summary (30 lines of text) One of the underappreciated aspects of neuronal biology is that, as postmitotically-differentiated neurons become mature, they undergo dynamic changes to ensure that the mature nervous system is capable of long- term survival and function. Understanding these mechanisms that are critical for the long-term homeostasis of the adult brain is important as their dysfunction could increase the vulnerability of neurons to age-related neurodegeneration. We have identified miR-29 as a microRNA that is strikingly induced with neuronal maturation. miR-29 is not detectable during embryonic development, but its levels are induced more than 300 fold by 2 months and even greater by 6 months in the adult brain. In contrast to the high miR-29 levels that are maintained in the normal adult brains, miR-29 levels are markedly reduced in Alzheimer’s Disease patients. miR-29 is recognized to target many of the genes in the AD pathways including BACE1, ADAM10, PICALM, and NAV3. To evaluate the functional importance of miR-29, we recently generated mice in which miR-29 can be conditionally deleted. Mice deficient for miR-29, either in the whole body or in the brain, are born normal but then progressively decline, exhibiting neurological defects and early lethality. These results show that miR-29 has an essential function in the mature brain. Our hypothesis is that miR-29, while not needed for embryonic development, is physiologically important for maintaining long-term homeostasis in the adult brain. Reduction in miR-29 levels could therefore increase the vulnerability of mature neurons to become dysfunctional in the context of Alzheimer’s Disease. The overall focus of our proposal is to understand the endogenous mechanisms that maintain the very high levels of miR-29 in the normal brain, to critically examine the function on miR-29 is the adult brain, and to evaluate the therapeutic potential of miR-29 for Alzheimer’s Disease. Specifically, in Aim 1, we will test the hypothesis is that an increase in miR-29 transcription in mature neurons is a result of chromatin derepression. Importantly, we will also examine whether the substantial increase in miR-29 is a consequence of increased processing and stability in mature neurons. In Aim 2, we will focus on defining the molecular, cellular and behavioral consequences of deleting miR-29 in the adult brain. To evaluate the therapeutic potential of miR- 29 for Alzheimer’s Disease, we have also generated mice in which miR-29 can be conditionally overexpressed. Thus in Aim 3, we will examine whether overexpression of miR-29 is beneficial in the mutant APP knock-in mouse model of Alzheimer’s Disease. Overall, we are excited to be working on a molecule, miR-29, that has a unique and essential function in the mature brain. Our studies will help define its mechanisms of action as well as evaluate its therapeutic potential in the context of Alzheimer’s Disease.