MicroRNA-based therapy for rheumatoid arthritis

基于 MicroRNA 的类风湿性关节炎疗法

• 批准号: 10208713
• 负责人: Salah-uddin Ahmed
• 金额: $ 32.91万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-12 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208713
• 关键词: Adjuvant; Adjuvant Arthritis; Antiinflammatory Effect; Biogenesis; Biotin; Clinical; Data; Disease; Enzymes; Epigenetic Process; Exoribonucleases; Fibroblasts; Genes; Genetic Transcription; Human; IL8 gene; In Vitro; Incidence; Inflammation; Interleukin-1 beta; Interleukin-6; Interstitial Collagenase; Joints; Knowledge; Label; Link; Malignant Neoplasms; Methods; MicroRNAs; Modeling; Molecular; Mus; Pathogenesis; Pathway Analysis; Play; Polyubiquitination; Process; Production; RNA Editing; Rattus; Regulation; Replacement Therapy; Rheumatoid Arthritis; Ribonucleases; Role; Sampling; Serum; Serum Markers; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; TNF gene; TRAF2 gene; Testing; Therapeutic; Tissues; Transferase; Transgenic Organisms; Ubiquitin; Untranslated RNA; Validation; base; cell type; collagenase 3; cytokine; efficacy evaluation; efficacy testing; efficacy validation; functional restoration; human model; in vivo; in vivo evaluation; molecular phenotype; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; restoration; success; therapeutic miRNA; transcriptome sequencing; ubiquitin-protein ligase; uridylate

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.

项目总结