Sex-specific regulation of microRNAs in Alzheimer Disease

阿尔茨海默病中 microRNA 的性别特异性调控

• 批准号: 10667123
• 负责人: Toni R. Pak
• 金额: $ 66.17万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667123
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; BRCA1 gene; Binding; Binding Sites; Biogenesis; Biological; Biological Assay; Brain; Brain region; Cells; Cognition; Complex; Data; Estradiol; Estrogen Receptor beta; Estrogens; Female; Incidence; Kinetics; Length; Link; Longevity; Maps; Mediating; Memory; MicroRNAs; Microprocessor; Molecular; Organ; Pathway interactions; Pattern; Postmenopause; Process; Proteins; Proteomics; RNASE3L gene; Regulation; Research; Sex Bias; Sex Differences; Signal Pathway; Signal Transduction; Specificity; Testing; Therapeutic; Time; Tissues; Trans-Activators; Transcript; Untranslated RNA; Woman; age effect; age related; aging brain; body system; deprivation; experimental study; hnRNP-H; men; normal aging; novel; posttranscriptional; sex; trafficking; treatment strategy

PROJECT SUMMARY Alzheimer’s Disease is more prevalent in women than men, yet a biological basis for this sex difference is not understood. The primary objective of this proposal is to understand how 17β-estradiol (E2) regulates microRNA (miR) biogenesis and stability across the lifespan and in Alzheimer’s Disease (AD). We hypothesize that dysregulation of E2-mediated miR expression in the aged brain leads to greater Alzheimer Disease risk in women. The studies proposed are focused on understanding how estrogens regulate these miRs to get a better understanding of their dysregulation in AD - specifically in women. This will address a major gap in our understanding because how E2 influences the components of the miR biogenesis pathway to regulate mature miR expression levels in a cell- and/or age-specific manner is unknown, despite several studies demonstrating temporal and cell-specific effects of E2 on miR expression in a variety of organ systems. Our prior studies demonstrated that E2 treatment altered the expression levels of a subset of miRs in the female brain, and the ability to regulate these miRs depended on age, brain region, and length of E2 deprivation (i.e., time post- menopause). Collectively the experiments in Aim 1 will test the hypothesis that E2 differentially mediates mature miR stability depending on age and in Alzheimer’s Disease. We will use miR degradation assays to determine whether age and/or E2 affect the rate of miR degradation and, using a proteomics approach, identify the cis- and trans-acting factors that regulate miR stability. Aim 2 will addresses mechanistically how a select subset of miRs could be specifically regulated by E2 post-transcription. We will test the hypothesis that hnRNP H binding to ERβ reduces its association with pri-miR transcripts, ERβ interacts with BRCA1 to differentially facilitate DROSHA complex assembly, and that these interactions are dependent on age and E2 treatment. Aim 3 will determine the effects of age and E2 on miR subcellular localization and assess disruption of E2- mediated miR subcellular localization in Alzheimer’s Disease. This aim will test the hypothesis that E2 facilitates subcellular trafficking of miRs, thereby impacting miR function. Moreover, we will test the hypothesis that miR subcellular localization changes across the lifespan and that normal age-related subcellular localization is disrupted in Alzheimer’s Disease. Impact: Understanding the basic molecular signaling pathways of E2 in the aging brain will help drive therapeutic advances and inform treatment strategies for women with Alzheimer’s Disease.

项目概要 阿尔茨海默病在女性中比男性更常见，但这种性别差异的生物学基础尚不明确 明白了。该提案的主要目的是了解 17β-雌二醇 (E2) 如何调节 microRNA (miR) 在整个生命周期和阿尔茨海默病 (AD) 中的生物发生和稳定性。我们假设 老年大脑中 E2 介导的 miR 表达失调导致阿尔茨海默病风险增加 女性。拟议的研究重点是了解雌激素如何调节这些 miR 以获得 更好地了解他们在 AD 中的失调——特别是女性。这将解决我们的一个重大差距 了解 E2 如何影响 miR 生物发生途径的组成部分以调节成熟 尽管多项研究表明，细胞和/或年龄特异性方式的 miR 表达水平尚不清楚 E2 对多种器官系统中 miR 表达的时间和细胞特异性影响。我们之前的研究 证明 E2 治疗改变了女性大脑中 miR 子集的表达水平，并且 调节这些 miR 的能力取决于年龄、大脑区域和 E2 剥夺的时间长度（即，E2 剥夺后的时间） 绝经）。目标 1 中的实验将共同检验 E2 差异介导的假设 成熟 miR 的稳定性取决于年龄和阿尔茨海默病。我们将使用 miR 降解测定来 确定年龄和/或 E2 是否影响 miR 降解率，并使用蛋白质组学方法确定 调节 miR 稳定性的顺式和反式作用因子。目标 2 将机械地解决如何选择 miR 的子集可以由 E2 转录后特异性调节。我们将检验 hnRNP 的假设 H 与 ERβ 的结合减少了其与 pri-miR 转录物的关联，ERβ 与 BRCA1 的相互作用存在差异 促进 DROSHA 复合体的组装，并且这些相互作用取决于年龄和 E2 治疗。 目标 3 将确定年龄和 E2 对 miR 亚细胞定位的影响并评估 E2-的破坏 介导 miR 在阿尔茨海默病中的亚细胞定位。这个目标将检验 E2 促进的假设 miR 的亚细胞运输，从而影响 miR 功能。此外，我们将检验 miR 的假设 亚细胞定位在整个生命周期中发生变化，并且正常的与年龄相关的亚细胞定位是 阿尔茨海默病中断。影响：了解 E2 的基本分子信号传导途径 衰老的大脑将有助于推动治疗进步，并为患有阿尔茨海默病的女性提供治疗策略 疾病。