MicroRNA-based therapy for rheumatoid arthritis

基于 MicroRNA 的类风湿性关节炎疗法

基本信息

  • 批准号:
    10475349
  • 负责人:
  • 金额:
    $ 15.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-12 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY MicroRNAs (miRNAs) are single stranded non-coding RNAs that have emerged as a novel posttranscriptional regulators in rheumatoid arthritis (RA) pathogenesis. However, recent studies provide evidence that in general there is an overall reduction in miRNA expression in disease states such as cancer and RA. While the rationale for developing miRNA therapeutics are conceptually similar to other inhibitory approaches, restoring the function of a miRNA by miRNA replacement is a less characterized, yet potential therapeutic option never tested in RA. Intriguingly, the underlying reasons for disrupted miRNA biogenesis and degradation processes in RA are not fully understood. Our recent finding provides evidence that miR-17 expression was significantly low in RA serum, synovial fibroblasts (SFs), and synovial tissues (STs), as well as in the serum and joints of adjuvant-induced (AIA) rats. RNA-sequencing analysis showed modulation of 664 genes by the restoration of miR-17 levels using precursor (pre)-miR-17 in human RASFs. Ingenuity pathway analysis of RNA-sequencing data identified the ubiquitin proteasome system in the TNF-α signaling pathway as a primary target of miR-17. Furthermore, the restoration of miR-17 levels using precursor-miR- 17 (pre-miR-17) reduced the ability of ubiquitin E3 ligase TRAF2 to associate with its signaling partner, cIAP2, thereby inhibiting TNF-α-induced downstream signal transduction pathways and suppressing the production of IL-6, IL-8, MMP-1, and MMP-13 in human RASFs. While these novel findings provide evidence for the impact of miR-17 replacement on posttranslational processes critical in TNF-α signaling in RASFs, several questions important to miR- 17 biogenesis and turnover remains unanswered, including the reasons for severely low expression in RA, the impact of proinflammatory cytokines on miR-17 biogenesis and turnover, and the relevance and efficacy of miR-17 replacement therapy in RA. Based on these novel observations, we propose that miR-17 replacement therapy could ameliorate RA. Thus, in specific aim 1, we will determine the deregulated mechanism of miR-17 biogenesis and turnover in RA. In aim 2, we will evaluate the relevance and molecular mechanisms of miR-17 restoration on TNF-α- induced molecular and phenotypic changes in human RASFs. Finally, aim 3 will test the in vivo efficacy of miR-17 delivery in TNF-α transgenic (hTNF-tg) mouse model and rat AIA model of human RA. The success of these studies will lead to two clinically distinct findings: 1) Elucidation of the altered miRNA biogenesis and turnover mechanism in RA pathogenesis, and 2) the validation of miRNA-based therapeutic approaches for the treatment of RA.
项目摘要 microRNA(miRNA)是单链非编码RNA,已成为新的转录后出现 类风湿关节炎(RA)发病机理中的调节剂。但是,最近的研究提供了总体上的证据 是癌症和RA等疾病状态中miRNA表达的总体降低。而理由 开发miRNA疗法在概念上与其他抑制方法相似,恢复了 miRNA由miRNA替代是一种较少的特征,但潜在的治疗选择从未在RA中进行测试。有趣的是, 尚未完全了解RA中miRNA生物发生和降解过程的干扰原因。 我们最近的发现提供了证据,表明miR-17的表达在RA血清,滑膜成纤维细胞中显着低 (SFS)和滑膜组织(STS),以及在调节诱导的(AIA)大鼠的血清和关节中。 RNA测序 分析显示了使用前体(PRE)-MIR-17在人类中对664个基因的调节 RASFS。 RNA测序数据的创新途径分析确定了TNF-α中的泛素蛋白酶体系统 信号通路作为miR-17的主要目标。此外,使用前体mir-恢复miR-17水平 17(MIR-17前)降低了泛素E3连接酶TRAF2与其信号伴侣CIAP2相关的能力 抑制TNF-α诱导的下游信号转移途径并抑制IL-6,IL-8, 人类RASF中的MMP-1和MMP-13。尽管这些新颖的发现为mir-17的影响提供了证据 替换在RASF中TNF-α信号中关键的翻译后过程中,对mir-重要的几个问题 17生物发生和营业额仍未得到解答,包括在RA中严重低表达的原因,影响 关于miR-17生物发生和周转率的促炎细胞因子,以及miR-17的相关性和效率 RA的替代疗法。基于这些新颖的观察,我们提出miR-17替代疗法可以 改善RA。在特定的目标1中,我们将确定miR-17生物发生的放松管制机制和 RA的营业额。在AIM 2中,我们将评估miR-17恢复TNF-α-的相关性和分子机制 诱导人RASF的分子和表型变化。最后,AIM 3将测试miR-17的体内效率 人类RA的TNF-α转基因(HTNF-TG)小鼠模型和大鼠AIA模型中的递送。这些研究的成功 将导致两个临床上不同的发现:1)阐明miRNA生物发生和周转机制的改变 RA发病机理和2)基于miRNA的治疗方法的验证RA治疗。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

Salah-uddin Ahmed的其他基金

MicroRNA-based therapy for rheumatoid arthritis
基于 MicroRNA 的类风湿性关节炎疗法
  • 批准号:
    10208713
    10208713
  • 财政年份:
    2018
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
MicroRNA-based therapy for rheumatoid arthritis
基于 MicroRNA 的类风湿性关节炎疗法
  • 批准号:
    10432053
    10432053
  • 财政年份:
    2018
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Novel targeted therapeutics for regulating synovial hyperplasia in RA
调节 RA 滑膜增生的新型靶向疗法
  • 批准号:
    9109868
    9109868
  • 财政年份:
    2016
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
RANTES/CCL5 mediated tissue remodeling in RA
RANTES/CCL5 介导的 RA 组织重塑
  • 批准号:
    9269866
    9269866
  • 财政年份:
    2016
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Regulation of IL-6 mediated inflammation and tissue destruction by EGCG
EGCG 对 IL-6 介导的炎症和组织破坏的调节
  • 批准号:
    8636996
    8636996
  • 财政年份:
    2013
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Regulation of IL-6 mediated inflammation and tissue destruction by EGCG
EGCG 对 IL-6 介导的炎症和组织破坏的调节
  • 批准号:
    8505768
    8505768
  • 财政年份:
    2013
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Regulation of IL-6 mediated inflammation and tissue destruction by EGCG
EGCG 对 IL-6 介导的炎症和组织破坏的调节
  • 批准号:
    9246432
    9246432
  • 财政年份:
    2013
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG
EGCG 抑制 CCR1/CCR5 介导的血管生成和关节破坏
  • 批准号:
    8016216
    8016216
  • 财政年份:
    2008
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG
EGCG 抑制 CCR1/CCR5 介导的血管生成和关节破坏
  • 批准号:
    7869352
    7869352
  • 财政年份:
    2008
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:
Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG
EGCG 抑制 CCR1/CCR5 介导的血管生成和关节破坏
  • 批准号:
    7513319
    7513319
  • 财政年份:
    2008
  • 资助金额:
    $ 15.3万
    $ 15.3万
  • 项目类别:

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