Biogenetical Mechanisms Underlying Individual miRNAs Associated with Alzheimer's Disease

与阿尔茨海默病相关的单个 miRNA 的生物遗传学机制

基本信息

批准号：
9764232
负责人：
Wenming Li
金额：
$ 23.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764232
关键词：
Address Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Attenuated Autopsy Biogenesis Brain Brain Diseases Cell physiology Cells Complex Coupled Data Dementia DiGeorge Syndrome Disease Elderly Enzymes Future Generations Genes Individual Intervention Legal patent MAPK14 gene Mediating Messenger RNA Methods Methyl-CpG-Binding Protein 2 MicroRNAs Microprocessor Molecular Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nuclear Outcome Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Patients Play Process Proteins Proteomics Public Health Quality of life Rattus Regulation Ribonuclease III Role Series Stress TP53 gene Techniques Testing Transcript Translations Treatment Efficacy Untranslated RNA abeta oligomer base beta-site APP cleaving enzyme 1 biological adaptation to stress disorder control drug development hyperphosphorylated tau intervention effect novel off-patent protein complex quality of death recruit research and development stress activated protein kinase tau Proteins therapeutic target

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is among the leading causes of a poor life quality and death in the elderly. No treatment available stops the progression of AD because of poor understanding of mechanisms underlying this disease. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of targeted mRNAs and play important roles in almost every critical cellular process. Also, multiple lines of evidence indicate that miRNAs are essential for neuron function and survival. Not surprisingly, alterations of individual miRNAs have been implicated in the AD pathological condition. The number of miRNAs is dysregulated in the AD conditions. Several neuroprotective miRNAs are markedly downregulated, while several neurodegenerative miRNAs are significantly upregulated in the same AD context. Identifying what reason causes the differentiative expressions of miRNAs may be key to the understanding of AD pathogenesis. MiRNA biogenesis is controlled by several tightly coupled sequential steps. What step of biogenesis is dysregulated under AD conditions? Our preliminary data have revealed that dysregulation of key AD-associated miRNAs occurs at their step from primary miRNAs (pri-miRNAs) to precursor miRNAs (pre-miRNAs). Nuclear RNase III enzyme Drosha with its partner DGCR8 forms the microprocessor complex and acts first in the cascade to process pri-miRNA transcripts into pre-miRNA transcripts. The microprocessor complex is highly regulated, but its regulation and mechanisms underlying individual miRNAs are poorly understood. In this project, based on our preliminary findings, we can confidently create a hypothesis that the altered proteins in individual miRNA microprocessor complexes by AD stress deregulate subset miRNA biogenesis and cause AD- associated pathological changes. We propose the following specific aims to test this hypothesis: Aim I: Determine how AD-associated miRNAs change at pri-, pre-, and mature levels in three level conditions; Aim II: Develop novel specific probe-based proteomics techniques to dissect differentiations of protein components; and Aim III: Identify altered proteins in microprocessor complex serving as regulators for miRNA biogenesis and determining the effect of intervention of regulators on AD-associated pathology. How AD-associated stress dysregulates microprocessor components may be crucial to understanding the neurodegenerative process in AD. A positive outcome of the proposed study will reveal biogenetical mechanisms underlying individual AD-associated miRNAs. Revealed novel regulators should serve as more effective therapeutic targets to address AD pathological processes. The findings will have a high impact on our understanding of the degenerative process of AD and possibly other neurodegenerative diseases.

项目摘要阿尔茨海默氏病（AD）是造成长期生活质量和死亡差的主要原因之一。不可用的治疗可以阻止AD的进展，因为对此机制的理解不足疾病。 microRNA（miRNA）是小的非编码RNA，可调节靶向mRNA的翻译和在几乎每个关键的细胞过程中都起着重要作用。另外，多行证据表明miRNA 对于神经元功能和生存至关重要。毫不奇怪，单个miRNA的改变已经在AD病理状况下实施。在AD条件下，miRNA的数量失调。一些神经保护miRNA明显下调，而几个神经退行性miRNA是在相同的广告上下文中大大更新。确定原因是什么原因引起的 miRNA的表达可能是理解AD发病机理的关键。 miRNA生物发生由几个紧密耦合的顺序步骤控制。生物发生的步骤是在AD条件下失调？我们的初步数据表明，关键广告相关的失调 miRNA出现在其从原发性miRNA（PRI-MIRNA）到前体miRNA（前MIRNA）的步骤。核 RNase III酶Drosha及其伴侣DGCR8形成了微处理器复合物，首先作用于级联将PRI-MIRNA转录物处理成前MIRNA转录本。微处理器复合物受到高度调节，但是，它的调节和基于个体miRNA的机制知之甚少。在这个项目中，基于在我们的初步发现中，我们可以自信地提出一个假设，即在个人中改变了蛋白质 miRNA微处理器复合物通过AD应力放松调节子集生物发生，并引起ad- 相关的病理变化。我们提出以下具体旨在检验这一假设的特定旨在：目的I：确定在三个级别条件下Pri-，Pre-Pre-和成熟水平上与AD相关的miRNA如何变化； AIM II：开发新型的基于探针的蛋白质组学技术来剖析蛋白质的分化成分; AIM III：确定微处理器复合物中改变的蛋白质，用作miRNA的调节剂生物发生并确定调节剂对AD相关病理的干预作用。广告相关的应力失调如何使微处理器组件对理解理解至关重要 AD中的神经退行性过程。拟议的研究的积极结果将揭示生物遗传学机制基本的单个广告相关miRNA。揭示的新型监管机构应该更有效治疗目标以解决AD病理过程。这些发现将对我们的了解AD的退化过程和可能的其他神经退行性疾病。