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

基本信息

  • 批准号:
    10577898
  • 负责人:
  • 金额:
    $ 58.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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
项目总结:

项目成果

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CLAIRE L MOORE其他文献

CLAIRE L MOORE的其他文献

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{{ truncateString('CLAIRE L MOORE', 18)}}的其他基金

The Role of alternative mRNA polyadenylation in SARS-CoV-2 replication & the host response
替代 mRNA 多聚腺苷酸化在 SARS-CoV-2 复制中的作用
  • 批准号:
    10450983
  • 财政年份:
    2022
  • 资助金额:
    $ 58.45万
  • 项目类别:
The Role of alternative mRNA polyadenylation in SARS-CoV-2 replication & the host response
替代 mRNA 多聚腺苷酸化在 SARS-CoV-2 复制中的作用
  • 批准号:
    10559623
  • 财政年份:
    2022
  • 资助金额:
    $ 58.45万
  • 项目类别:
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:
    10357895
  • 财政年份:
    2020
  • 资助金额:
    $ 58.45万
  • 项目类别:
Tufts IRACDA
塔夫茨大学 IRACDA
  • 批准号:
    10248365
  • 财政年份:
    2019
  • 资助金额:
    $ 58.45万
  • 项目类别:
Tufts IRACDA
塔夫茨大学 IRACDA
  • 批准号:
    10478087
  • 财政年份:
    2019
  • 资助金额:
    $ 58.45万
  • 项目类别:
Regulation of eukaryotic mRNA polyadenylation by sustained stress
持续应激对真核 mRNA 多腺苷酸化的调节
  • 批准号:
    9055727
  • 财政年份:
    2015
  • 资助金额:
    $ 58.45万
  • 项目类别:
Molecular mechanism of mRNA 3'-end formation in yeast
酵母中mRNA 3端形成的分子机制
  • 批准号:
    7988814
  • 财政年份:
    2009
  • 资助金额:
    $ 58.45万
  • 项目类别:
Training in Education and Critical Research Skills
教育和批判性研究技能培训
  • 批准号:
    7871572
  • 财政年份:
    2009
  • 资助金额:
    $ 58.45万
  • 项目类别:
High throughput screening for anti-fungal drugs that inhibit mRNA polyadenylation
高通量筛选抑制 mRNA 多腺苷酸化的抗真菌药物
  • 批准号:
    7685457
  • 财政年份:
    2008
  • 资助金额:
    $ 58.45万
  • 项目类别:
High throughput screening for anti-fungal drugs that inhibit mRNA polyadenylation
高通量筛选抑制 mRNA 多腺苷酸化的抗真菌药物
  • 批准号:
    7359292
  • 财政年份:
    2008
  • 资助金额:
    $ 58.45万
  • 项目类别:

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