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

基本信息

批准号：
7990606
负责人：
CATHERINE L CLELLAND
金额：
$ 20.53万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990606
关键词：
Age Algorithms Alzheimer&apos 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 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

项目摘要

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 tau 病阿尔茨海默病 (AD) 和额颞叶痴呆 (FTD) 的特征是细胞内含有 tau 的神经原纤维缠结 (NFT) 积聚，以及进行性认知功能障碍和神经元死亡。对 tau/tta-4510 小鼠诱导性 tau 病模型的研究非常模仿人类疾病的特征，结果表明，在 NFT 形成之前，中间 tau 物质的早期积累会促进导致神经元功能障碍和记忆丧失的事件。 miRNA 是一类广泛存在的小 RNA，参与转录后调节，最近的研究数据表明，一些 miRNA 在涉及学习和记忆的神经元过程中具有特定的调节作用。这项拟议的研究旨在检验以下假设：tau 诱导的 tau/tta-4510 模型中 miRNA 的早期失调会导致这些小鼠出现认知缺陷。这项拟议研究背后的基本原理是基于我们令人兴奋的试点数据，该数据显示多种 miRNA，包括 miR-138（调节突触形成）在 tau/tta 小鼠中失调，这些小鼠被设计为表达突变 tau 转基因，并且与认知缺陷相比与年龄匹配的对照小鼠。此外，在最初的试点研究中发现的许多失调的miRNA也在人类AD大脑中异常表达，并且与缠结负荷显着相关。为了检验我们的假设，在目标 1 下，我们建议 a) 通过微阵列测量老年小鼠 tau 蛋白病模型中的 miRNA 水平，利用我们暂时抑制模型中转基因表达的能力来识别那些参与认知和神经退行性变的 miRNA，而不是那些相关的 miRNA b) 与人类 FTD 大脑中差异表达 miRNA 的数据集进行比较，以 c) 识别物种之间一致且具有临床相关性的 miRNA。在目标 2 下，目标 1 下定义的 miRNA 将在早期 tau 聚集物种开始在小鼠大脑中积累期间以及认知能力下降开始期间（1 个月、2.5 个月和 4 个月）进行临时测量，但之前导致广泛的神经元丢失和缠结形成。然后，我们将使用 LCM 来确认与对照（PHF1 阴性）相比，前缠结神经元（PHF1 阳性）中暂时失调的 miRNA 也发生了类似的改变。在目标 3 下，我们还将使用综合实验和计算方法来识别暂时失调 miRNA 的功能 mRNA 靶点。在转染 Pre-miR 或抗 miR 寡核苷酸后，在神经元细胞系中发现失调的 mRNA，并通过 SEED 序列分析和指定的功能相关性预测为靶标，然后将在小鼠 tau/tta 皮质 PHF1 阳性中进行验证和负神经元作为 miRNA 调节的目标。公共健康相关性：这项探索性研究的成功完成将导致临床相关 miRNA 的鉴定，这些 miRNA 在人类 tau 病相关神经病理学的发展过程中失调，并导致人类 tau 病（如 FTD 和 AD）中出现的认知能力下降。我们还将鉴定这些失调 miRNA 的 mRNA 靶点。阐明 miRNA 在 tau 蛋白病中的潜在作用可能最终有助于开发能够延迟 FTD 和 AD 等疾病发作的药物。同样，在成功识别出预防 miRNA 失调和相关认知缺陷的新靶标后，预防疾病和/或其进展可能成为可能，并且与 NIH 的使命具有特殊的相关性。