Role of microRNA in regulating Fe, Amyloid, and Tau (FeAT) in Alzheimer's disease

microRNA 在阿尔茨海默病中调节 Fe、淀粉样蛋白和 Tau (FeAT) 的作用

• 批准号: 10460800
• 负责人: DEBOMOY K LAHIRI
• 金额: $ 63.02万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460800
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anatomy; Attention; Binding; Biological; Brain; Brain region; Cell physiology; Cities; Clinical; Clinical Trials; Data; Dementia; Diagnostic; Disease; Elements; Enzymes; Equilibrium; Eye; Failure; Goals; Homeostasis; Immunoprecipitation; Inflammation; Iron; Lead; MAPT gene; Mediating; Messenger RNA; Metabolic; MicroRNAs; Modeling; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Participant; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Pharmacology; Physiological; Play; Proteins; Regulation; Regulatory Pathway; Reporter; Research; Role; Sampling; Site; Supplementation; Symptoms; System; Testing; Time; Transgenic Mice; Translating; Translations; Untranslated RNA; Untranslated Regions; Wild Type Mouse; age related; balance testing; chelation; cohort; crosslink; gene product; improved; in vivo; iron metabolism; man; mouse model; neurobiological mechanism; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; outcome prediction; prevent; protein expression; response; symptomatic improvement; synergism; tau Proteins; tau expression; therapeutic target; tool; transgenic model of alzheimer disease

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder; available therapies only modestly improve symptoms. Our goal is to identify neurobiological mechanisms leading to neurodegeneration in AD. MicroRNAs (miRNA) are endogenous noncoding RNA molecules that typically silence translation. Little research exists on roles of miRNAs that target gene products implicated in AD as participants in neurobiology. We recently discovered a miRNA (miR346) that stimulates translation of amyloid-β precursor protein (APP) as part of iron (Fe) homeostasis. This miRNA binds a site that overlaps an iron responsive element (IRE) in APP. miR346 also has a predicted site in the tau 3’-UTR, and tau facilitates APP activity in Fe homeostasis. Also, we have identified miR298 reducing levels of APP and a specific tau protein moiety. The proposal objective is to test “balancing feat” among miR346, miR298, Fe, and cellular inflammation networks via APP and tau (FeAT). Our central hy- pothesis is 1) miR346 plays a vital role in maintaining Fe homeostasis; 2) Manipulating miRNA could redirect Fe metabolism to prevent or treat AD and other neurodegenerative disorders. SA1: Test hypothesis—miR346 and 298 interact with APP and tau mRNA untranslated region (UTR) se- quences. Rationale: Fe dyshomeostasis is implicated in AD. APP and tau play roles in Fe metabolism. A co- regulator of both that also takes part in Fe metabolism could be a vital tool for preventing AD-related neurotoxi- city. Impact: Studies reveal miR346 and miR298 coregulate APP and tau. SA2: miR346 and 298 regulation of APP and tau both leads to and responds to Fe dyshomeostasis. Rationale: We intend to establish specific mechanisms of miR346 and miR298 activity within Fe metabolism. miR298 will be indirectly involved in response to Fe levels. Identifying the role of miRNA-mediated regulation within this network should elucidate miRNA-dependent mechanisms for pharmacological manipulation. Impact: These studies are likely to reveal novel biological mechanisms for miRNA function and FeAT trio regulation. SA3: Test hypothesis—miR346 and 298 are dysregulated in AD in stage and brain region specific man- ners. Rationale: We will identify partners of FeAT with miR346 and miR298 in well-characterized clinical sam- ples. We expect regulation to vary in anatomical- and pathology-dependent patterns. Impact: These studies in AD patients will further establish the miRNAs as therapeutic targets. SA4: Translate miR346 and miR298 manipulation on Fe homeostasis, APP and tau, and critical pro- cessing enzymes in transgenic AD model mice. Rationale: We intend to ascertain how or if AD pathology affects the interaction and how the interaction affects AD pathology. We will pay particular attention to differences in response to miRNAs or blockade in wild type vs. transgenic mice. Impact: Determining how manipulation of miR346 in both normal and induced pathology systems will alter pertinent protein levels with an eye toward reducing pathology via miR346 control.

阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病；可用的治疗方法很有限 改善症状。我们的目标是确定导致 AD 神经变性的神经生物学机制。 MicroRNA (miRNA) 是内源性非编码 RNA 分子，通常会沉默翻译。研究很少 存在于 miRNA 的作用上，这些 miRNA 靶向与 AD 相关的基因产物，作为神经生物学的参与者。我们最近 发现了一种 miRNA (miR346)，它可以刺激淀粉样蛋白-β 前体蛋白 (APP) 翻译为铁的一部分 （Fe）体内平衡。该 miRNA 结合的位点与 APP 中的铁反应元件 (IRE) 重叠。 miR346 也 在 tau 3'-UTR 中有一个预测位点，tau 促进 Fe 稳态中的 APP 活性。此外，我们还确定了 miR298 降低 APP 和特定 tau 蛋白部分的水平。该提案的目标是测试“平衡 通过 APP 和 tau (FeAT) 在 miR346、miR298、Fe 和细胞炎症网络之间实现“壮举”。 假设 1) miR346 在维持 Fe 稳态中发挥着至关重要的作用； 2) 操纵 miRNA 可以改变 Fe 的方向 代谢来预防或治疗 AD 和其他神经退行性疾病。 SA1：测试假设 — miR346 和 298 与 APP 和 tau mRNA 非翻译区 (UTR) 相互作用 序列。理由：AD 涉及 Fe 体内平衡失调。 APP 和 tau 在 Fe 代谢中发挥作用。一个共同 两者的调节因子也参与铁代谢，可能是预防 AD 相关神经毒性的重要工具。 城市。影响：研究表明 miR346 和 miR298 共同调节 APP 和 tau。 SA2：miR346 和 298 对 APP 和 tau 的调节都会导致 Fe 稳态失调并对其做出反应。 理由：我们打算建立铁代谢中 miR346 和 miR298 活性的特定机制。 miR298 将间接参与对 Fe 水平的反应。确定 miRNA 介导的调节作用 该网络内应阐明 miRNA 依赖性药理学操作机制。影响： 这些研究可能揭示 miRNA 功能和 FeAT 三重奏调控的新生物学机制。 SA3：测试假设 — miR346 和 298 在 AD 阶段和大脑区域特定的人中失调 书呆子。理由：我们将在充分表征的临床样本中确定 FeAT 与 miR346 和 miR298 的合作伙伴 请。我们预计监管会因解剖学和病理学依赖性模式而有所不同。影响：这些研究 AD患者将进一步确立miRNA作为治疗靶点。 SA4：翻译 miR346 和 miR298 对 Fe 稳态、APP 和 tau 以及关键亲的操纵 转基因 AD 模型小鼠中的酶的终止。理由：我们打算确定 AD 病理如何或是否存在 影响相互作用以及相互作用如何影响 AD 病理。我们会特别注意差异 野生型与转基因小鼠对 miRNA 或阻断的反应。影响：确定如何操纵 正常和诱导病理系统中的 miR346 都会改变相关蛋白质水平，着眼于 通过 miR346 控制减少病理。