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.

阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病。可用的疗法仅适度 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）是通常沉默翻译的内源性非编码RNA分子。很少的研究 存在于针对AD中作为神经生物学参与者实施的基因产品的miRNA的作用。我们最近 发现了一个miRNA（miR346），该miRNA作为铁的一部分刺激了淀粉样蛋白β前体蛋白（APP）的翻译 （FE）体内平衡。该miRNA结合了一个在应用程序中与铁反应元件（IRE）重叠的位点。也是mir346 在Tau 3’-UTR中有一个预测的站点，在F​​E稳态中有Tau Favorite App活动。另外，我们已经确定了 miR298降低APP的水平和特定的Tau蛋白部分。建议目标是测试“平衡 Mir346，MiR298，Fe和细胞炎症网络中的壮举”，通过App和Tau（壮举）。 pothesis是1）miR346在维持FE稳态中起着至关重要的作用； 2）操纵miRNA可以重定向Fe 预防或治疗AD和其他神经退行性疾病的代谢。 SA1：检验假设-MIR346和298与App和Tau mRNA未翻译区（UTR）se-相互作用 理由：Fe Dyshomeostasis在AD中实施。 App和Tau在FE代谢中扮演角色。共同 也参与FE代谢的调节剂可能是预防与广告相关的神经毒素的重要工具 城市。影响：研究揭示了MiR346和MiR298 Coregulate App和Tau。 SA2：MIR346和298 APP和TAU的调节都会导致并响应Fe Dyshomeostasis。 理由：我们打算在Fe代谢中建立MIR346和MIR298活性的特定机制。 MiR298将间接参与响应Fe水平。确定miRNA介导的调节的作用 在该网络中，应阐明对药物操纵的miRNA依赖机制。影响： 这些研究可能揭示了miRNA功能和壮举三重奏调控的新型生物学机制。 SA3：检验假设 - MIR346和298在阶段和大脑区域特定的阶段和大脑区域的AD中失调 ners。理由：我们将在特征良好的临床SAM中确定与MiR346和MiR298的壮举合作伙伴 ples。我们预计调节在解剖学和病理依赖性模式中会有所不同。影响：这些研究 AD患者将进一步建立miRNA作为治疗靶标。 SA4：翻译MiR346和MiR298对FE稳态，App和Tau的操纵，以及批判性Pro- 转基因AD模型小鼠中的塞式酶。理由：我们打算确定AD病理学如何或是否 影响相互作用以及相互作用如何影响AD病理。我们将特别注意差异 响应miRNA或野生型与转基因小鼠的阻滞。影响：确定如何操纵 在正常和诱导病理系统中，miR346都会改变相关蛋白水平，以注视 通过miR346控制减少病理。