Essential Function of miR-29 in the Mature Brain

miR-29 在成熟大脑中的基本功能

• 批准号: 9904306
• 负责人: Mohanish P Deshmukh
• 金额: $ 52.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904306
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Apoptosis; Apoptotic; Attention; Behavioral; Biology; Birth; Brain; Brain Injuries; Cerebellum; Cessation of life; Chromatin; Defect; Development; Embryo; Embryonic Development; Ensure; Event; Exhibits; Family; Functional disorder; Gene Expression; Genes; Genetic Transcription; Histologic; Homeostasis; Individual; Knock-in Mouse; Link; Maintenance; MicroRNAs; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Trauma; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurologic Deficit; Neuronal Dysfunction; Neurons; Pathway interactions; Patients; Peripheral Nervous System; Physiological; Predisposition; Production; Seizures; Small RNA; Testing; Text; Therapeutic; Transgenic Mice; abeta accumulation; age related neurodegeneration; behavioral outcome; beta-site APP cleaving enzyme 1; conditional knockout; derepression; disability; experimental study; healthy aging; improved; in vivo; member; mouse model; mutant; nervous system disorder; neurotoxicity; overexpression; postnatal; prevent; transcriptome sequencing

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.

项目摘要（30行文本） 神经元生物学的一个未被充分认识的方面是，作为有丝分裂后分化的神经元， 成熟后，它们会发生动态变化，以确保成熟的神经系统能够长时间地 长期生存和功能。了解这些机制是至关重要的长期稳态 成年人的大脑是重要的，因为他们的功能障碍可能会增加神经元对年龄相关的脆弱性。 神经变性 我们已经确定miR-29是一种在神经元成熟过程中显著诱导的microRNA。miR-29是 在胚胎发育期间检测不到，但其水平在2个月时诱导超过300倍， 在6个月大的成年人大脑中甚至更大。与维持在高水平的miR-29相比， 在正常成人大脑中，miR-29水平在阿尔茨海默病患者中显著降低。miR-29是 被认为靶向AD途径中的许多基因，包括BACE 1、ADAM 10、PICALM和NAV 3。 为了评估miR-29的功能重要性，我们最近产生了miR-29可以在小鼠中表达的小鼠。 有条件删除。无论是在全身还是在大脑中缺乏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致死性。这些结果表明，miR-29 在成熟的大脑中起着重要的作用我们的假设是，miR-29，虽然不是胚胎发育所必需的， 发育，对于维持成人大脑的长期稳态具有生理学重要性。 因此，miR-29水平的降低可能会增加成熟神经元的脆弱性， 在老年痴呆症的背景下功能失调。 我们的建议的总体重点是了解维持非常高的内生机制， 正常大脑中miR-29的水平，严格检查miR-29在成人大脑中的功能， 评估miR-29对阿尔茨海默病的治疗潜力。具体而言，在目标1中，我们将测试 一种假设是成熟神经元中miR-29转录的增加是染色质去阻遏的结果。 重要的是，我们还将研究miR-29的大幅增加是否是由于miR-29的增加而导致的。 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 成年人大脑中删除miR-29的行为后果。为了评估miR-1的治疗潜力， 对于阿尔茨海默病，我们还产生了其中miR-29可以条件性过表达的小鼠。 因此，在目标3中，我们将检查miR-29的过表达是否在突变APP敲入中是有益的。 阿尔茨海默病的小鼠模型。 总的来说，我们很高兴能够研究一种分子，miR-29，它具有独特的和重要的功能， 成熟的大脑我们的研究将有助于确定其作用机制，以及评估其治疗 在阿尔茨海默病的背景下的潜力。