Regulation of plasma LDL and HDL by microRNA-541-3p

microRNA-541-3p 对血浆 LDL 和 HDL 的调节

• 批准号: 10733641
• 负责人: M Mahmood Hussain
• 金额: $ 63.19万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733641
• 关键词: 3' Untranslated Regions; Affect; Anti-Inflammatory Agents; Antiatherogenic; Antioxidants; Apolipoproteins; Apolipoproteins B; Applications Grants; Atherosclerosis; Binding Sites; Blood; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Complex; Enhancers; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Libraries; Lipids; Lipoproteins; Low-Density Lipoproteins; Messenger RNA; MicroRNAs; Molecular; Mus; Mutate; Orthologous Gene; Output; Pathway interactions; Physiological; Plasma; Primary carcinoma of the liver cells; Production; Property; Proteins; RNA; Regulation; Reporting; Repression; Role; Site; Testing; Transcriptional Regulation; Untranslated RNA; Zinc Fingers; cardiovascular disorder risk; cardiovascular risk factor; combat; drug development; gene repression; hepatoma cell; in vivo; mRNA Transcript Degradation; mutant; new therapeutic target; novel; posttranscriptional; prevent; promoter; protein expression; transcription factor

High LDL and low HDL levels are risk factors for cardiovascular disease. Our long-term goal is to identify and explain mechanisms through which microRNAs (miRs) regulate plasma lipoprotein levels. Here, we report the identification of a novel miR-541-3p that decreases ApoB secretion and increases ApoA1 secretion in human hepatoma cells. Furthermore, we show that miR-541-3p regulates the zinc finger (Znf) transcription factors (TFs) zinc finger 101 (Znf101) and castor zinc finger protein 1 (Casz1), thereby modulating the expression of ApoB and ApoA1, respectively. On the basis of these novel findings, the following aims focus on elucidating how miR- 541-3p regulates the expression of these TFs, and how these TFs regulate ApoB and ApoA1 expression. Furthermore, we plan to establish the roles of these TFs in the control of plasma lipoproteins and atherosclerosis. Aim 1. Establish that miR-541-3p enhances post-transcriptional degradation of Znf101 and Casz1 mRNA by interacting with 3´-untranslated region (UTR) sequences. We propose to establish that RNA-RNA interactions between miR-541-3p and Znf101/Casz1 mRNAs are necessary for the regulation of mRNA levels and show that miR-541-3p interacts with target sequences in the 3´-UTR, thereby enhancing mRNA degradation. Aim 2. Explain the mechanism of regulation of ApoB and ApoA1 expression by Znf101 and Casz1 in human and mouse liver cells. We plan to elucidate how Znf101 and Casz1 regulate transcription of the APOB and APOA1 genes. We propose to show that Znf101 is an enhancer of APOB gene transcription, and Casz1 is a repressor of APOA1 gene transcription. Furthermore, we plan to clarify the roles of mouse orthologs of these TFs in the transcriptional regulation of mouse Apob and Apoa1 genes. These studies should reveal the molecular underpinnings of the regulation of ApoB and ApoA1 by miR-541-3p. Aim 3. Elucidate the roles of Zfp961 (mouse ortholog of human Znf101) and Casz1 in the regulation of plasma LDL, HDL, and atherosclerosis in mice. In these in vivo studies, we will investigate the physiological roles of ApoB and ApoA1 regulation by the TFs identified and characterized in the earlier aims. We will interrogate whether regulation of ApoB and ApoA1 by these TFs decreases LDL levels, increases HDL levels, and diminishes atherosclerosis. These studies should demonstrate that transcriptional regulation of ApoB and ApoA1 leads to an anti-atherogenic profile in mice. This proposal is based on our discovery of a novel miR-541-3p that regulates the expression of ApoB and ApoA1 in opposite directions through two newly identified TFs. After completion of the proposed studies, we expect to: (1) elucidate how miR-541-3p regulates various TFs; (2) explain the molecular mechanisms through which these TFs regulate APOB and APOA1 transcription; and (3) establish the physiological importance of the identified molecules and mechanisms in the regulation of plasma lipoproteins and atherosclerosis. These genes and mechanisms may serve as new therapeutic targets to prevent and treat cardiovascular disease.

高低密度脂蛋白和低高密度脂蛋白水平是心血管疾病的危险因素，我们的长期目标是识别和诊断。 解释 microRNA (miR) 调节血浆脂蛋白水平的机制在此，我们报告了。 鉴定出一种新型 miR-541-3p，可减少人体内 ApoB 分泌并增加 ApoA1 分泌 此外，我们发现 miR-541-3p 调节锌指 (Znf) 转录因子 (TF)。 锌指 101 (Znf101) 和蓖麻锌指蛋白 1 (Casz1)，从而调节 ApoB 的表达 分别基于这些新发现，以下目标集中于阐明 miR- 是如何发挥作用的。 541-3p 调节这些 TF 的表达，以及这些 TF 如何调节 ApoB 和 ApoA1 表达。 此外，我们计划确定这些转录因子在控制血浆脂蛋白和动脉粥样硬化中的作用。 目标 1. 确定 miR-541-3p 增强 Znf101 和 Casz1 mRNA 的转录后降解 我们建议通过与 3´-非翻译区 (UTR) 序列相互作用来建立 RNA-RNA。 miR-541-3p 和 Znf101/Casz1 mRNA 之间的相互作用对于 mRNA 水平的调节是必要的 并表明 miR-541-3p 与 3´-UTR 中的靶序列相互作用，从而增强 mRNA 降解。 目的 2. 解释 Znf101 和 Casz1 调控 ApoB 和 ApoA1 表达的机制 我们计划阐明 Znf101 和 Casz1 如何调节 APOB 的转录。 我们建议证明 Znf101 是 APOB 基因转录的增强子，而 Casz1 是 APOA1 基因转录的抑制因子 此外，我们计划阐明这些小鼠直系同源物的作用。 这些研究应该揭示小鼠 Apob 和 Apoa1 基因转录调控中的 TF。 miR-541-3p 调节 ApoB 和 ApoA1 的基础。 目标 3. 阐明 Zfp961（人 Znf101 的小鼠直系同源物）和 Casz1 在调节中的作用 小鼠血浆低密度脂蛋白、高密度脂蛋白和动脉粥样硬化在这些体内研究中，我们将研究其生理学。 我们将在之前的目标中确定和表征 TF 的 ApoB 和 ApoA1 调节作用。 询问这些 TF 对 ApoB 和 ApoA1 的调节是否会降低 LDL 水平，增加 HDL 水平， 这些研究应该证明 ApoB 和的转录调节。 ApoA1 在小鼠中具有抗动脉粥样硬化作用。 该提案基于我们发现了一种新型 miR-541-3p，可调节 ApoB 和 ApoA1 的表达 通过两个新确定的 TF 在相反的方向上完成拟议的研究后，我们期望： (1) 阐明 miR-541-3p 如何调节各种 TF；(2) 解释这些转录因子的分子机制； TF 调节 APOB 和 APOA1 转录；(3) 确定已识别的生理重要性； 血浆脂蛋白和动脉粥样硬化调节的分子和机制。 机制可能作为预防和治疗心血管疾病的新治疗靶点。