Administrative Supplement: Neurobiological role of MicroRNA in Alzheimer's

行政补充：MicroRNA 在阿尔茨海默病中的神经生物学作用

• 批准号: 9321507
• 负责人: DEBOMOY K LAHIRI
• 金额: $ 15.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321507
• 关键词: Abeta synthesis; Address; Administrative Supplement; Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Biological; Brain; Cells; Clinical Trials; Dementia; Deposition; Disease; Disease Progression; Drug Targeting; Elderly; Elements; Enzymes; Etiology; Failure; Gene Expression Regulation; Genes; Goals; Health; Homeostasis; Human; Impaired cognition; Iron; Iron Regulatory Protein 1; Lead; Link; Mediating; Messenger RNA; MicroRNAs; Molecular; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Pathology; Pathway interactions; Patients; Pattern; Peptides; Phase; Physiological; Play; Post-Transcriptional Regulation; Process; Production; Property; Protein Precursors; Proteins; RNA Interference; Regulation; Regulatory Pathway; Research; Rodent; Rodent Model; Role; Sampling; Site; Specificity; Symptoms; Testing; Therapeutic Agents; Transcript; Transgenic Animals; Transgenic Mice; Translations; Untranslated RNA; Untranslated Regions; Work; base; beta secretase; beta-site APP cleaving enzyme 1; cell type; cohort; disorder control; fetal; gene correction; gene product; improved; in vivo; member; mimicry; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; protein expression; secretase; therapeutic target; transcriptome

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Because current treatments provide modest symptomatic relief and do not slow AD progression, a better understanding of molecular bases of AD pathology is needed. This proposal will identify and validate microRNAs (miRNAs) as a new class of drug targets. miRNAs are endogenous, short, non-coding RNAs that typically inhibit protein expression by interacting with specific recognition elements of target transcripts. AD is believed to result from overproduction of amyloid-ß peptide (Aß), derived from Aß precursor protein (APP), and dysregulation of proteins involved in Aß production (e.g. APP, ß-secretase/BACE1) contributes to excess Aß deposition. We have also recently found that miRNA can stimulate APP expression in interaction with iron homeostasis. We propose to study APP and BACE1 regulation by miRNA. We hypothesize specific miRNAs regulate endogenous levels of APP and BACE1, are dysfunctional in AD, and manipulation will reduce Aß. Specific Aim 1(SA1) will identify functional miRNA target sites in APP and BACE1 and validate miRNA post-transcriptional regulation of native APP and BACE1 expression. Rationale: Discover functional miRNA targets in UTRs of APP and BACE1 transcripts using. Endpoints are APP and BACE1 mRNA & proteins, and Aß peptides, which we predict to change with miRNA. Impact: Manipulation of miRNA regulation is a novel therapeutic approach and may be feasible for correcting gene dysregulation in AD. SA2 will test physiological interactions between miRNA validated in SA1 and their regulatory networks over APP and BACE1 expression. Rationale: Test other mechanisms of regulation likely linked to maintain homeostasis of APP, BACE1 and Aß. Identifying roles of miRNA in this network is vital to pharmacologically target miRNA-transcript interactions. Impact: Reveal novel mechanisms for miRNA function in AD. SA3 will assess effects of in vivo manipulation of validated miRNA in AD animal models. Rationale: Test our validated miRNAs as therapeutic targets in AD transgenic animals, including interaction with iron homeostasis, by inducing miRNA-dependent changes in translation. Impact: Validate specific miRNAs as drug targets in vivo and identify novel AD-related regulatory networks. SA4 will examine whether miRNAs implicated in regulatory control of gene products involved in Aß homeostasis are dysregulated in AD patients. Rationale: In SA1-3, we will identify pertinent miRNAs that modulate expression of gene products implicated in Aß production. If these miRNAs are also involved in AD pathology, we expect their regulation to vary in anatomical- and pathology-dependent patterns. Impact: Further demonstrate validity of miRNAs as therapeutic targets to treat AD-related dysregulation. Research dictated by our central hypothesis could cause a significant paradigm shift on the field by elucidating novel regulatory mechanisms and identifying specific miRNAs that regulate important gene products implicated in AD. Final impact will be in eventual use of these new drug targets to produce therapeutic agents to slow or halt progression in AD.

 描述（由适用提供）：阿尔茨海默氏病（AD）是古老的痴呆症最常见的原因。由于当前的治疗可提供适度的症状缓解，并且不会减慢AD的进展，因此需要更好地了解AD病理学的分子碱基。该提案将确定并验证microRNA（miRNA）为新的药物靶标。 miRNA是内源性的，短的，非编码的RNA，通常通过与靶转录物的特定识别元素相互作用来抑制蛋白质表达。据信AD是由衍生自Aß前体蛋白（APP）的淀粉样蛋白-β肽（Aß）产生的过量产生的，以及参与Aß产生的蛋白质的失调（例如App，β-分泌酶/BACE1）会导致过量Aß沉积。我们最近还发现，miRNA可以在与铁稳态相互作用时刺激APP表达。我们建议通过miRNA研究APP和BACE1调控。我们假设特定的miRNA调节APP和BACE1的内源水平，AD功能失调，操作将减少Aß。特定的目标1（SA1）将在APP和BACE1中识别功能性miRNA目标位点，并验证MIRNA的本机App和Bace1表达的转录后调节。理由：使用APP和BACE1转录本中的UTR中的功能miRNA靶标。终点是APP和BACE1 mRNA和蛋白质，以及Aß肽，我们预计将使用miRNA改变。影响：miRNA调节的操纵是一种新型的治疗方法，可能可用于纠正AD中的基因失调。 SA2将测试SA1中验证的miRNA与APP上的调节网络和BACE1表达之间的生理相互作用。理由：测试其他调节机制可能与维持APP，BACE1和Aß的体内平衡有关。鉴定miRNA在该网络中的作用对于药物对miRNA转录相互作用至关重要。影响：揭示了AD中miRNA功能的新型机制。 SA3将评估在AD动物模型中对经过验证的miRNA操纵的影响。理由：通过诱导翻译中的miRNA依赖性变化，将我们经过验证的miRNA作为AD转基因动物的治疗靶标，包括与铁稳态的相互作用。影响：验证特定的miRNA作为体内药物靶标，并确定与广告相关的新型调节网络。 SA4将检查MIRNA是否在AD患者的Aß稳态控制基因产品的调节控制中是否实施。理由：在SA1-3中，我们将确定相关的miRNA调节Aß产量实施的基因产物的表达。如果这些miRNA也参与AD病理学，我们希望它们的调节在解剖学和病理依赖性模式中会有所不同。影响：进一步证明了miRNA作为治疗广告相关失调的治疗靶标的有效性。通过我们的中心假设决定的研究可能会通过阐明新型调节机制并识别调节AD中实施重要基因产物的特定miRNA来引起该领域的显着范式转移。最终影响将是最终使用这些新药物来生产治疗剂以减慢或停止AD的进展。