Temporal Changes in MicroRNA Function During Tau tangle Accumulation

Tau 缠结积累过程中 MicroRNA 功能的时间变化

• 批准号: 8091292
• 负责人: CATHERINE L CLELLAND
• 金额: $ 16.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091292
• 关键词: Age; Aging; Algorithms; Alzheimer' s Disease; Appearance; Biological Process; Brain; Cell Line; Cells; Cessation of life; Cognition; Cognitive deficits; Data; Data Set; Dendritic Spines; Development; Diagnosis; Disease; Engineering; Event; Frontotemporal Dementia; Funding; Genes; Human; Human Development; Impaired cognition; Lead; Learning; Literature; Measures; Memory; Memory Loss; Messenger RNA; MicroRNAs; Mission; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Oligonucleotides; Pathogenesis; Pathway Analysis; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Post-Transcriptional Regulation; Process; RNA; Reporting; Role; Sampling; Screening procedure; Seeds; Sequence Analysis; Severity of illness; Site; Small RNA; Tauopathies; Temporal Lobe; Testing; Time; Tissues; Transfection; Transgenes; Transgenic Organisms; United States National Institutes of Health; abstracting; aged; base; clinically relevant; cognitive function; design; human disease; laser capture microdissection; mRNA Expression; neurofibrillary tangle formation; neuron loss; neuropathology; prevent; public health relevance; synaptogenesis; tau Proteins; tau aggregation; tau mutation; transgene expression

DESCRIPTION (provided by applicant): The neurodegenerative tauopathies Alzheimer's disease (AD) and Frontotemporal dementia (FTD), are characterized by the intracellular build-up of tau-containing neurofibrillary tangles (NFT), and progressive cognitive dysfunction and neuron death. Studies of the tau/tta-4510 mouse inducible tauopathy model, which closely mimics features of the human diseases, have shown that early accumulation of intermediate-tau species, prior to the formation of NFTs, promote the events leading to neuronal dysfunction and memory loss. miRNAs are a widespread class of small RNAs involved in post-transcriptional regulation, and data from recent studies have illustrated a specific regulatory role for some miRNAs during the neuronal processes involved in learning and memory. This proposed study is designed to test the hypothesis that tau-induced early dysregulation of miRNAs in the tau/tta-4510 model results in the cognitive deficits observed in these mice. The rationale behind this proposed study is based on our exciting pilot data showing multiple miRNAs, including miR-138 (that regulates synapse formation) are dysregulated in tau/tta mice engineered to express the mutant tau transgene and that manifest with cognitive deficits, when compared to age-matched control mice. In addition, many of the dysregulated miRNAs found in the initial pilot study are also abnormally expressed in the human AD brain and are significantly correlated with tangle load. To test our hypothesis, Under Aim 1 we propose to a) Measure miRNA levels in the aged murine tauopathy model via microarrays, utilizing our ability to temporally suppress transgene expression in the model to identify those miRNAs involved in cognition and neurodegeneration rather than those which correlate with NFT accumulation, and b) Compare to datasets of differentially expressed miRNAs in human FTD brains, to c) Identify miRNAs that are concordant between the species and have clinical relevance. Under Aim 2, the miRNAs defined under Aim 1 will be measured temporally during the period that early tau aggregated species begin to accumulate in the murine brain, plus during the onset of cognitive decline (1 month, 2.5 months and 4 months), but prior to extensive neuron loss and tangle formation. We will then use LCM to confirm that temporally dysregulated miRNAs are similarly altered in pre-tangle neurons (PHF1 positive), when compared to controls (PHF1negative). Under Aim 3 we will also identify the functional mRNA targets of the temporally dysregulated miRNAs, using an integrated experimental and computational approach. mRNAs found to be dysregulated in a neuronal cell line, following transfection of Pre-miR or anti-miR oligonucleotides, and also predicted as targets via SEED sequence analysis and assigned functional relevance, will then be validated in the murine tau/tta cortical PHF1 positive and negative neurons as miRNA- regulated targets. PUBLIC HEALTH RELEVANCE: The successful completion of this exploratory study will lead to the identification of clinically relevant miRNAs that are dysregulated during the development of human tauopathy-associated neuropathology and contribute to the cognitive decline seen in human tauopathies such as FTD and AD. We will also identify the mRNA targets of these dysregulated miRNAs. Elucidating the potential role of miRNAs in tauopathy may ultimately allow for the development of medications that can delay, for example, the onset of FTD and AD. Similarly, preventing the diseases and/or their progression, may become a possibility following the successful identification of new targets to prevent miRNA dysregulation and the associated cognitive deficits, and is of exceptional relevance to the mission of the NIH.

描述（由申请人提供）：神经退行性的tauopathies阿尔茨海默氏病（AD）和额颞痴呆（FTD）的特征是含有TAU神经纤维纤维缠结（NFT）的细胞内积累，以及渐进的认知功能障碍和神经元死亡。 TAU/TTA-4510小鼠诱导型大型病模型的研究紧密模仿了人类疾病的特征，它表明，在形成NFTS之前，中间TAU物种的早期积累促进了导致神经元功能障碍和记忆损失的事件。 miRNA是参与转录后调节的一类普遍类别的小型RNA，最近的研究数据表明，在学习和记忆中涉及的神经元过程中，某些miRNA的特定调节作用。这项拟议的研究旨在检验以下假设：TAU诱导的MiRNA早期失调在TAU/TTA-4510模型中导致这些小鼠观察到的认知缺陷。这项拟议的研究背后的理由是基于我们令人兴奋的试点数据，显示了多个miRNA，包括miR-138（调节突触形成）在tau/tta小鼠中不调节，该小鼠设计用于表达突变体tau thau thau trangene并与认知缺陷表现出来，当到年龄匹配的对照小鼠。此外，在最初的初步研究中发现的许多失调的miRNA在人AD脑中也异常表达，并且与缠结载荷显着相关。为了检验我们的假设，在目标1下，我们提出a）通过微阵列测量老化的鼠tauopathy模型中的miRNA水平，利用我们的能力抑制模型中的转基因表达以识别那些与认知和神经变性有关的miRNA，而不是相关的miRNA随着NFT的积累，b）与人类FTD大脑中差异表达的miRNA的数据集进行比较，c）识别物种之间一致并具有临床相关性的miRNA。在AIM 2下，在AIM 1下定义的miRNA将在tau早期聚集物种开始在鼠大脑中积聚的时间内进行时间测量，加上认知能力下降开始（1个月，2.5个月和4个月），但事先广泛的神经元丧失和缠结形成。然后，我们将使用LCM来确认与对照组相比，在缠结神经元（PHF1阳性）中类似地变化的miRNA也会改变。在AIM 3下，我们还将使用集成的实验和计算方法来确定时间失调的miRNA的功能mRNA靶标。在转染前MIR或抗MIR寡核苷酸后，发现在神经元细胞系中发现的mRNA失调，并且还将通过种子序列分析和分配的功能相关性预测为靶标，然后在Murine Tau/tta Cortical PHF1阳性阳性中验证和负神经元作为miRNA调控靶标。 公共卫生相关性：这项探索性研究的成功完成将导致识别临床相关的miRNA，这些miRNA在人类陶氏病相关的神经病理学的发展过程中被失调，并促进了诸如FTD和AD等人类tauopathies的认知下降。我们还将确定这些失调的miRNA的mRNA靶标。阐明miRNA在tauopathy中的潜在作用可能最终允许开发有可能延迟FTD和AD发作的药物。同样，防止疾病和/或它们的进展，在成功识别新靶标以防止miRNA失调和相关的认知缺陷之后，可能成为可能性，并且与NIH的使命具有非凡的相关性。