Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)

阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导

• 批准号: 8307767
• 负责人: WALTER J LUKIW
• 金额: $ 29.11万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307767
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein Precursor; Antigen-Antibody Complex; Area; Astrocytes; Binding; Biological; Brain; Cells; Cellular Stress; Chronic; Clinical Management; Complement Activation; Complement Factor H; Complex; Country; Down-Regulation; Evolution; Exhibits; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Goals; Healthcare; Human; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Investigation; Link; Mediating; Messenger RNA; MicroRNAs; Microglia; Molecular Genetics; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligonucleotides; Outcome; Pathway interactions; Peptides; Phosphotransferases; Population; Process; Production; RNA Interference; Regulator Genes; Role; Severity of illness; Signal Pathway; Signal Transduction; Stress; System; TNF gene; Testing; Tg2576; Tissues; Transcription Factor AP-1; Translating; Up-Regulation; aging brain; amyloid peptide; amyloidogenesis; base; brain cell; cytokine; design; human IRAK1 protein; human PHEMX protein; interleukin-1 receptor-associated kinase; mouse model; neuropathology; neurotoxic; neurotrophic factor; secretase; stem; transgenic model of alzheimer disease

DESCRIPTION (provided by applicant): Abundant evidence supports the idea that progressive up-regulation of complex pro-inflammatory signaling, A¿42 peptide evolution, and loss of neurotrophic support underlie the initiation and propagation of Alzheimer's disease (AD). Micro RNA (miRNA)-mediated messenger RNA (mRNA) interference is a newly discovered genetic mechanism involved in the regulation of gene expression at the post-transcriptional level. The major mode of miRNA action is to target and bind to the 3' un-translated region of specific mRNAs and in doing so, quench expression of that mRNA, thereby acting as a negative regulator of gene expression. AD affects only specific areas of the brain, and mis-regulated miRNA expression is strongly linked to altered gene expression within these regions. In AD models, these same AD-enriched miRNAs induce specific pathological changes that are strikingly similar to those observed in AD brain. Accumulating evidence strongly suggests that altered miRNA-mediated processing of specific mRNA populations triggers the pathogenic expression of genes that drive the AD process. The overall goal of this project is to significantly move the miRNAin- AD field forward, and impact the scientific understanding of AD, by defining mechanistically how specific miRNAs induce molecular-genetic mechanisms that result in AD-type change. Human brains utilize only a fraction of all known miRNA species; and only a subset of these are altered in AD brain. Increases in the expression of a specific NF-?B-sensitive miRNA-146a down-regulates the abundance of at least three major mRNA targets, complement factor H (CFH), interleukin-1 receptor associated kinase (IRAK) and tetraspanin 12 (TSPAN12), that encode key modulators of the brain's innate immune system, inflammatory response and the generation of neurotrophic or neurotoxic amyloid peptides. Down-regulated TSPAN12 restricts ADAM10 (a-secretase) dependent cleavage of beta-amyloid precursor protein (¿APP). Stressed human brain cells up-regulate miRNA-146a in parallel with increased amyloidogenesis and shedding of A¿42 peptides. Hypothesis: up-regulated miRNA-146a contributes to altered innate immune and inflammatory responses, increased A¿42 peptide generation and decreased neurotrophic support. Three Specific Aims test predicted outcomes based on this hypothesis in AD, in stressed human brain primary cells, and in specific transgenic models of AD. These Specific Aims include (1) identification of alterations in miRNA-146a abundance in AD brain; (2) testing whether stressed human neuronal, astrocyte or microglial cells exhibit miRNA changes similar to those conducive to inflammatory neurodegeneration and A¿42 peptide generation in AD tissues, and testing if added exogenous miRNA-146a or anti-miRNA-146a oligonucleotides will promote or neutralize these changes; and (3) testing whether miRNA-146a, anti-miRNA-146a and modulation of CFH, IRAK or TSPAN12 expression are key regulators of the inflammatory response and amyloidogenesis in amyloid over-expressing Tg2576 mice.

描述（由申请人提供）：大量证据支持以下观点：复杂促炎信号传导的渐进性上调、A 42肽进化和神经营养支持的丧失是阿尔茨海默病（AD）的起始和传播的基础。微RNA（microRNA，miRNA）介导的信使RNA（messenger RNA，mRNA）干扰是一种新发现的在转录后水平调控基因表达的遗传机制。miRNA作用的主要模式是靶向并结合特定mRNA的3'非翻译区，并且在这样做时，淬灭该mRNA的表达，从而充当基因表达的负调节剂。AD仅影响大脑的特定区域，并且错误调节的miRNA表达与这些区域内的基因表达改变密切相关。在AD模型中，这些相同的AD富集的miRNA诱导与AD脑中观察到的那些惊人相似的特定病理变化。越来越多的证据有力地表明，特定mRNA群体的改变的miRNA介导的加工触发了驱动AD过程的基因的致病性表达。该项目的总体目标是通过机械地定义特定miRNA如何诱导导致AD类型变化的分子遗传机制，显著推动miRNAin-AD领域的发展，并影响对AD的科学理解。人类大脑仅利用所有已知miRNA种类的一小部分;并且仅其中的一个子集在AD大脑中被改变。在特定的NF-？B-敏感性miRNA-146 a下调至少三种主要mRNA靶标的丰度，补体因子H（CFH）、白细胞介素-1受体相关激酶（IRAK）和四跨膜蛋白12（TSPAN 12），其编码脑先天免疫系统、炎症反应和神经营养性或神经毒性淀粉样肽的产生的关键调节剂。下调的TSPAN 12限制β-淀粉样前体蛋白（APP）的ADAM 10（α-分泌酶）依赖性切割。应激人脑细胞上调miRNA-146 a，同时增加淀粉样蛋白生成和A 42肽脱落。假设：上调的miRNA-146 a有助于改变先天免疫和炎症反应，增加A42肽的产生和减少神经营养支持。三个特定目标测试预测结果的基础上，在AD，在强调人脑原代细胞，并在特定的转基因模型的AD的这一假设。这些特定目的包括（1）鉴定AD脑中miRNA-146 a丰度的改变;（2）测试应激的人神经元、星形胶质细胞或小胶质细胞是否表现出与AD组织中有助于炎性神经变性和A42肽产生的miRNA变化相似的miRNA变化，并测试添加的外源性miRNA-146 a或抗miRNA-146 a寡核苷酸是否会促进或中和这些变化;和（3）测试miRNA-146 a、抗miRNA-146 a和CFH、IRAK或TSPAN 12表达的调节是否是淀粉样蛋白过表达Tg 2576小鼠中炎症反应和淀粉样蛋白生成的关键调节剂。