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Uridylation of miRNAs by ZCCHC6 Regulates IL-6 Expression in Arthritis

Uridylation of miRNAs by ZCCHC6 Regulates IL-6 Expression in Arthritis
ZCCHC6 对 miRNA 的尿苷化调节关节炎中 IL-6 的表达
批准号:
9041542
负责人:
Tariq M Haqqi
金额:
$58.04万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-04-01 至 2020-03-31

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英文摘要
 DESCRIPTION (provided by applicant): Abstract An estimated 27 million Americans age 25 and older have osteoarthritis (OA), a degenerative disease of articular cartilage characterized by loss of the cartilage matrix, mainly collagen and proteoglycans, leading to joint tissue destruction and loss of function. Before age 45, more men than women have osteoarthritis; after age 45, it is more common in women. The pro-inflammatory cytokine IL-6 has recently gained interest due to its elevated levels in synovial fluid and sera from OA patients and its capacity to upregulate the expression of MMP-13 and inhibit the expression of type-II collagen. Mature miRNAs are non-coding RNAs that inhibit the translation and stability of target mRNAs and are now known to undergo addition of non-template nucleotides (largely uridines) to the 3' ends (3'NTAs). The enzymes responsible for 3' end modifications of miRNAs have only recently been identified in cancer and immune cells but have not yet been described in cartilage or chondrocytes. Our preliminary data show that (1) ZCCHC6-a nucleotidyl transferase-is highly expressed in damaged OA cartilage; and (2) regulates IL-6 expression in human chondrocytes. ZCCHC6 is known to uridylate mRNAs thus suggesting that ZCCHC6-mediated miRNA 3'end modifications could play a significant role in the post-transcriptional regulation of IL-6, and possibly of other inflammatory mediators, in OA. We will pursue 4 specific aims to test the fundamental hypothesis that ZCCHC6 uridylates mature miRNAs in chondrocytes to regulate IL-6 expression and inflammation in OA. Specific Aim-1. Studies will test the hypothesis that "cytokine targeting miRNAs are uridylated in OA cartilage". Specific Aim-2. We will test the hypothesis that "miRNA uridylation abrogates repression of IL-6 expression in human OA chondrocytes". Specific Aim-3. We will test the hypothesis that "expression of ZCCHC6 is essential for IL-6 expression in human OA chondrocytes". Specific Aim-4. In an animal model of human OA we will test the hypothesis that "ZCCHC6 mediates miRNA uridylation and regulate IL-6 expression during the induction and progression of the disease". Knowledge gained from these studies will be important since by understanding how miRNA 3'end modifications affect the expression of inflammatory mediators in OA may lead to the development of novel biomarkers and therapies for the effective treatment of OA.
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会议论文
Mechanism of ZCCHC6 Regulation of Mitochondrial Dysfunction In Alzheimer's Disease
Identification of Plasma microRNA Expression Profile in Ankylosing Spondylitis.
  • 批准号:
    8770784
  • 项目类别:
  • 资助金额:
    $19.87万
  • 财政年份:
    2014
  • 负责人:
    Tariq M Haqqi
  • 依托单位:
Identification of Plasma microRNA Expression Profile in Ankylosing Spondylitis.
  • 批准号:
    8907904
  • 项目类别:
  • 资助金额:
    $15.89万
  • 财政年份:
    2014
  • 负责人:
    Tariq M Haqqi
  • 依托单位:
Suppression of SHH Expression in Arthritis by Butea monosperma
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