Neurobiological Role of MicroRNA in Alzheimer's

MicroRNA 在阿尔茨海默病中的神经生物学作用

• 批准号: 9134034
• 负责人: DEBOMOY K LAHIRI
• 金额: $ 31.97万
• 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/9134034
• 关键词: Abeta synthesis; Address; 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（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆的最常见原因。由于目前的治疗只能适度缓解症状，并且不能减缓 AD 的进展，因此需要更好地了解 AD 病理学的分子基础。该提案将鉴定并验证 microRNA (miRNA) 作为一类新的药物靶点。 miRNA 是内源性、短的、非编码 RNA，通常通过与目标转录物的特定识别元件相互作用来抑制蛋白质表达。 AD 被认为是由 Aß 前体蛋白 (APP) 衍生的淀粉样蛋白-ß 肽 (Aß) 过量产生所致，而参与 Aß 产生的蛋白质（例如 APP、ß-分泌酶/BACE1）失调会导致 Aß 过量沉积。我们最近还发现 miRNA 可以刺激 APP 表达并与铁稳态相互作用。我们建议研究 miRNA 对 APP 和 BACE1 的调节。我们假设特定的 miRNA 调节 APP 和 BACE1 的内源水平，在 AD 中功能失调，并且操作会降低 Aß。具体目标 1 (SA1) 将识别 APP 和 BACE1 中的功能性 miRNA 靶位点，并验证 miRNA 对天然 APP 和 BACE1 表达的转录后调控。理由：使用 APP 和 BACE1 转录本的 UTR 发现功能性 miRNA 靶点。终点是 APP 和 BACE1 mRNA 和蛋白质，以及 Aß 肽，我们预测它们会随着 miRNA 的变化而变化。影响：操纵 miRNA 调节是一种新颖的治疗方法，对于纠正 AD 中的基因失调可能是可行的。 SA2 将测试 SA1 中验证的 miRNA 及其对 APP 和 BACE1 表达的调控网络之间的生理相互作用。理由：测试可能与维持 APP、BACE1 和 Aß 稳态相关的其他调节机制。识别 miRNA 在该网络中的作用对于药理学靶向 miRNA-转录本相互作用至关重要。影响：揭示 miRNA 在 AD 中发挥功能的新机制。 SA3 将评估 AD 动物模型中经过验证的 miRNA 的体内操作效果。理由：通过诱导 miRNA 依赖性的翻译变化，测试我们验证的 miRNA 作为 AD 转基因动物的治疗靶点，包括与铁稳态的相互作用。影响：验证特定 miRNA 作为体内药物靶点并确定新的 AD 相关调控网络。 SA4 将检查与 Aß 稳态相关的基因产物的调控有关的 miRNA 在 AD 患者中是否失调。理由：在 SA1-3 中，我们将鉴定调节 Aß 生产中涉及的基因产物表达的相关 miRNA。如果这些 miRNA 也参与 AD 病理学，我们预计它们的调节会因解剖学和病理学依赖性模式而变化。影响：进一步证明 miRNA 作为治疗 AD 相关失调的治疗靶点的有效性。我们的中心假设所主导的研究可能会通过阐明新的调控机制并识别调节与 AD 相关的重要基因产物的特定 miRNA 来引起该领域的重大范式转变。最终的影响将是最终利用这些新药物靶点来生产治疗药物，以减缓或阻止 AD 的进展。