Defining the Role of Alternative Polyadenylation in Macrophage Differentiation and Function

定义替代多腺苷酸化在巨噬细胞分化和功能中的作用

• 批准号: 10577898
• 负责人: CLAIRE L MOORE
• 金额: $ 58.45万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577898
• 关键词: 3' Untranslated Regions; Abate; Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Antigen Presentation; Binding Sites; Biology; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Code; Consensus; Data; Degenerative Disorder; Disease; Effector Cell; Ensure; Gene Expression Regulation; Genes; Genetic Transcription; Global Change; Goals; Immune system; Infection; Inflammatory; Innate Immune System; Knowledge; Length; Macrophage; Malignant Neoplasms; Maps; Messenger RNA; Microbe; Mission; Modeling; Molecular; Pathology; Pathway interactions; Pattern; Phagocytosis; Play; Poly A; Poly(A) Tail; Polyadenylation; Polyadenylation Pathway; Positioning Attribute; Process; Production; Proliferating; Protein Isoforms; Proteins; RNA; RNA Stability; Regulation; Reporter; Research; Role; Sequence Analysis; Site; Survival Rate; System; Tail; Testing; Therapeutic; Tissues; Translations; United States National Institutes of Health; cell type; cytokine; design; experience; genome-wide; human disease; immunoregulation; knock-down; leukemia; mRNA Precursor; migration; neoplastic cell; novel; novel therapeutics; overexpression; polyadenylated messenger RNA; posttranscriptional; precursor cell; protein function; response; tissue repair; tool; transcriptome sequencing; treatment strategy; trend; tumor progression; whole genome; 3' Untranslated Regions; Abate; Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Antigen Presentation; Binding Sites; Biology; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Code; Consensus; Data; Degenerative Disorder; Disease; Effector Cell; Ensure; Gene Expression Regulation; Genes; Genetic Transcription; Global Change; Goals; Immune system; Infection; Inflammatory; Innate Immune System; Knowledge; Length; Macrophage; Malignant Neoplasms; Maps; Messenger RNA; Microbe; Mission; Modeling; Molecular; Pathology; Pathway interactions; Pattern; Phagocytosis; Play; Poly A; Poly(A) Tail; Polyadenylation; Polyadenylation Pathway; Positioning Attribute; Process; Production; Proliferating; Protein Isoforms; Proteins; RNA; RNA Stability; Regulation; Reporter; Research; Role; Sequence Analysis; Site; Survival Rate; System; Tail; Testing; Therapeutic; Tissues; Translations; United States National Institutes of Health; cell type; cytokine; design; experience; genome-wide; human disease; immunoregulation; knock-down; leukemia; mRNA Precursor; migration; neoplastic cell; novel; novel therapeutics; overexpression; polyadenylated messenger RNA; posttranscriptional; precursor cell; protein function; response; tissue repair; tool; transcriptome sequencing; treatment strategy; trend; tumor progression; whole genome

Project Summary: Macrophages are key effector cells of the immune system, with critical functions in killing of microbes, production of inflammatory regulators, and tissue repair. However, an excessive macrophage response contributes to the pathology of cancer as well as inflammatory and degenerative diseases. In addition, unchecked proliferation of macrophage precursors in lieu of differentiation leads to acute myeloid leukemia. To better address how to modulate macrophage function to help abate diseases that involve changes in macrophage biology, we must understand the critical molecular pathways that govern macrophage differentiation and regulate their activity. We propose that one of these pathways will involve mRNA polyadenylation, an essential maturation step in which mRNA precursor is trimmed at its 3' end and a poly(A) tail (pA) added. Changing the position of the pA site through a process called alternative polyadenylation (APA) plays an important, increasingly appreciated role in regulation of gene expression. Shortening of the 3' untranslated region can remove regulatory sequences that control RNA stability, translation, and subcellular localization, whereas coding region shortening can dramatically alter protein function. While global changes in APA have been observed in tumor progression and other types of cellular differentiation, the contribution of APA to macrophage differentiation has not been studied. We hypothesize that a global shift in APA is required for macrophage differentiation and that this shift is driven by changing levels of APA regulators. Our objective is to determine how APA contributes to macrophage differentiation, with the long-range goal of defining how this might be manipulated in therapeutic settings to promote differentiation and modulate macrophage function. Our specific aims will 1) determine the global pattern of APA during macrophage differentiation, the functional classes of genes impacted by APA, and sequence features that might characterize these sites, 2) define drivers of macrophage APA and the consequence that altering their expression has on differentiation as well as well-characterized macrophage functions such as cytokine production, migration, and phagocytosis, and 3) determine the molecular mechanisms that alter the levels of the proteins that regulate APA. Because macrophage are a first line of defense for many diseases and dysregulation of their differentiation leads to leukemias, our proposed studies should ultimately inform new therapeutic tools to modulate macrophage production. They will also broadly advance our understanding of general and tissue-specific APA paradigms. s

项目摘要： 巨噬细胞是免疫系统的关键效应细胞，具有杀死微生物的关键功能， 炎症调节剂和组织修复的产生。但是，巨噬细胞反应过多 有助于癌症的病理以及炎症和退化性疾病。此外， 巨噬细胞前体的不受组织的扩散代替分化导致急性髓样白血病。到 更好地解决如何调节巨噬细胞功能以帮助减轻涉及变化的疾病 巨噬细胞生物学，我们必须了解控制巨噬细胞的临界分子途径 分化和调节其活动。 我们建议这些途径之一将涉及mRNA聚腺苷酸化，这是一个必不可少的成熟步骤 mRNA前体在其3'端进行修剪，并添加了poly（a）尾巴（PA）。改变PA的位置 通过称为替代聚腺苷酸化（APA）的过程扮演着重要的，越来越多的欣赏 在基因表达调节中的作用。缩短3'未翻译区域可以消除调节性 控制RNA稳定性，翻译和亚细胞定位的序列，而编码区域 缩短可以极大地改变蛋白质功能。虽然在肿瘤中观察到APA的全局变化 进展和其他类型的细胞分化，APA对巨噬细胞分化的贡献 尚未研究。 我们假设巨噬细胞分化需要全球APA的全球转变，并且这种转变是 由APA调节器的变化驱动。我们的目标是确定APA如何贡献 巨噬细胞的分化，其远程目标是定义如何在治疗中操纵这一点 促进分化和调节巨噬细胞功能的设置。我们的具体目标将确定 巨噬细胞分化过程中APA的全局模式，受APA影响的基因的功能类别， 以及可能表征这些位点的序列特征，2）定义巨噬细胞APA的驱动因素和 结果是改变其表达在分化以及特征巨噬细胞方面具有 细胞因子产生，迁移和吞噬作用等功能，以及3）确定分子 改变调节APA的蛋白质水平的机制。因为巨噬细胞是 我们的拟议研究 最终应告知新的治疗工具以调节巨噬细胞的生产。他们也将广泛 促进我们对一般和组织特异性APA范式的理解。 s