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（文本30行） 神经元生物学的基本方面之一是，作为森林分化后的神经元 变得成熟，他们会经历动态变化，以确保成熟的神经系统能够长期 术语生存和功能。了解这些对于长期稳态至关重要的机制 成人大脑很重要，因为他们的功能障碍可能会增加神经元与年龄相关的脆弱性 神经变性。 我们已经将miR-29鉴定为神经元成熟引起的惊人诱导的microRNA。 mir-29是 在胚胎发育过程中无法检测到，但其水平在2个月前诱导了300倍以上，并且 在成人大脑中，甚至更大。与在 正常的成年大脑，在阿尔茨海默氏病患者中，miR-29水平明显降低。 mir-29是 公认的目标是针对AD途径中的许多基因，包括BACE1，ADAM10，PICALM和NAV3。 为了评估miR-29的功能重要性，我们最近生成了miR-29的小鼠 有条件删除。在全身或大脑中缺乏miR-29的小鼠天生正常，但 然后逐渐衰落，表现出神经系统缺陷和早期致死性。这些结果表明miR-29 在成熟的大脑中具有重要功能。我们的假设是miR-29，虽然胚胎不需要 发展对于维持成人大脑的长期稳态至关重要。 因此，miR-29水平的降低可能会增加成熟神经元的脆弱性 在阿尔茨海默氏病的背景下功能失调。 我们提案的总体重点是了解保持非常高的内源性机制 正常大脑中miR-29的水平，批判性地检查miR-29的功能是成年大脑，而对 评估miR-29对阿尔茨海默氏病的治疗潜力。具体来说，在AIM 1中，我们将测试 假设是成熟神经元中miR-29转录的增加是染色质消除的结果。 重要的是，我们还将检查miR-29的大幅增长是否是增加的结果 成熟神经元的加工和稳定性。在AIM 2中，我们将专注于定义分子，细胞和 在成人大脑中删除miR-29的行为后果。评估miR-的治疗潜力 29对于阿尔茨海默氏病，我们还产生了小鼠，其中miR-29可以有条件地表达。 在AIM 3中，我们将检查miR-29的过表达是否对突变体应用程序敲入有益 阿尔茨海默氏病小鼠模型。 总体而言，我们很高兴能在一个分子MiR-29上工作，该分子在 成熟的大脑。我们的研究将有助于定义其作用机理并评估其治疗 在阿尔茨海默氏病的背景下的潜力。