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

• 批准号: 9507156
• 负责人: Wenming Li
• 金额: $ 19.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507156
• 关键词: Address; Affect; Alzheimer' 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; protein complex; quality of death; recruit; research and development; stress activated protein kinase; tau Proteins; therapeutic target

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.

项目概要 阿尔茨海默病 (AD) 是老年人生活质量差和死亡的主要原因之一。 由于对潜在机制了解甚少，可用的治疗可阻止 AD 的进展 MicroRNA (miRNA) 是调节目标 mRNA 翻译的小非编码 RNA。 此外，多种证据表明 miRNA 在几乎每个关键的细胞过程中都发挥着重要作用。 对于神经元功能和生存至关重要，单个 miRNA 的改变已经不足为奇。 与 AD 病理状况有关 miRNA 的数量在 AD 状况下失调。 神经保护性 miRNA 显着下调，而一些神经退行性 miRNA 则显着下调。 确定导致差异的原因。 miRNA 的表达可能是理解 AD 发病机制的关键。 miRNA 生物发生由几个紧密耦合的连续步骤控制。生物发生的步骤是什么。 AD 条件下失调？我们的初步数据显示，AD 相关的关键失调 miRNA 发生在从初级 miRNA (pri-miRNA) 到前体 miRNA (pre-miRNA) 的过程中。 RNase III 酶 Drosha 与其伙伴 DGCR8 形成微处理器复合体并在级联中首先起作用 将 pri-miRNA 转录物加工成 pre-miRNA 转录物 微处理器复合物受到高度调控， 但在这个项目中，对单个 miRNA 的调控和机制知之甚少。 根据我们的初步发现，我们可以自信地提出一个假设，即个体中的蛋白质 AD 应激导致的 miRNA 微处理器复合体解除了 miRNA 子集生物发生的调节并导致 AD- 我们提出以下具体目标来检验这一假设： 目标 I：确定 AD 相关 miRNA 在三个水平条件下如何在初级、前期和成熟水平发生变化； 目标二：开发基于探针的新型蛋白质组学技术来剖析蛋白质的差异 目标 III：识别微处理器复合体中作为 miRNA 调节因子的改变蛋白 生物发生并确定调节剂干预对 AD 相关病理的影响。 与 AD 相关的压力如何使微处理器组件失调可能对于理解 AD 相关的压力至关重要 AD 的神经退行性过程将揭示生物遗传机制。 揭示的个体 AD 相关 miRNA 应该更有效。 解决 AD 病理过程的治疗目标将对我们产生重大影响。 了解 AD 和可能的其他神经退行性疾病的退行性过程。