Mechanism of Long Non-coding RNAs Action in leiomyoma

长链非编码RNA在平滑肌瘤中的作用机制

• 批准号: 10330338
• 负责人: OMID A. KHORRAM
• 金额: $ 8.66万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330338
• 关键词: Age; Anti-Inflammatory Agents; Antiinflammatory Effect; Asthma; Benign; Biomedical Research; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cells; Development; Extracellular Matrix; Family; Fibroid Tumor; Funding; Genes; Goals; H19 gene; In Vitro; Inflammation; Inflammatory; Japan; Knowledge; Korea; Laboratories; Learning; Leiomyoma; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Porifera; Reporting; Role; Techniques; Testing; Therapeutic; Tranilast; Untranslated RNA; Uterine Fibroids; Woman; Work; career; falls; in vivo; next generation sequencing; reproductive; tumor

Uterine leiomyoma (fibroids) are benign tumors afflicting a significant number of reproductive age women and without a known cause. Our laboratory has focused on understanding how miRNAs impact pro-inflammatory and pro-fibrotic pathways in leiomyoma, and identified two miRNAsmiR-200c and miR-29c which primarily target cell cycle, inflammation and extracellular matrix (ECM) component genes respectively as key in the development of leiomyoma. Our recent findings using next generation sequencing has demonstrated a whole host of non-coding RNAs including long non-coding RNAs (lncRNAs) are dysregulated in fibroids. LncRNAs can act as sponge for miRNAs and therefore may be a driver of gene dysregulation in leiomyomas. Our previous work demonstrated that tranilast, an anti- inflammatory drug approved for the treatment of asthma in Japan and Korea, has potent effects in fibroid cells by inhibiting cell proliferation and stimulating the expression of two key miRNAs that are down regulated in fibroids (miR-200c and miR-29c)15, 16. These key miRNAs play a pivotal role in fibroid pathogenesis by targeting the expression of cell cycle regulatory proteins and inflammation (miR-200c), and composition and remodeling of the ECM (miR-29c). Furthermore, recent reports showed that H19 also can act as sponge for miR-29 and miR-200 family18-20 in various malignancies. In this project we propose to determine if H19 can act as a sponge for miR-29/miR-200 family in fibroids and if tranilast can decrease the expression of H19 and thereby increase the expression of miR-29 and miR-200 family. This project clearly falls within the scope of our R01 funded project exploring the interaction of H19 with miR-29 and miR-200 family. We hypothesize that H19 sponges miR-29 and miR-200 family in fibroids and that tranilast upregulates the expression of miR-29/miR-200 family by inhibiting the expression of H19. This hypothesis will be tested in two Aims. Aim 1: Determine if lncRNA H19 functions as a sponge for miR-29 and miR-200 family in fibroids, and determine the effects of tranilast on the expression of H19 in vitro and in vivo. Aim 2: Determine if the effect of tranilast on the expression of miR-29 and miR-200 family is mediated by H19. Completion of these aims will not only advance our knowledge of the role of long non-coding RNAs in fibroid pathogenesis and potential targeting them as a therapeutic approach but will also provide the opportunity for our candidate Mr. Quintanilla to learn a host of new molecular and surgical techniques and prepare him for a career in the biomedical research.

子宫平滑肌瘤（肌瘤）是影响大量复制年龄的良性肿瘤 妇女，没有已知原因。我们的实验室专注于了解miRNA如何影响 平滑肌瘤的促炎和纤维化途径，并鉴定 miR-29c主要靶细胞周期，注射和细胞外基质（ECM）成分 基因分别是平滑肌瘤发展的关键。我们最近使用下一代的发现 测序显示了包括长非编码RNA的大量非编码RNA （LNCRNA）在纤维中失调。 lncrnas可以充当miRNA的赞助商，因此可能是 平滑肌瘤基因失调的驱动力。我们以前的工作表明，Transilast是一种反 - 批准在日本和韩国治疗哮喘的炎症药物对 肌瘤细胞通过抑制细胞增殖并刺激两个关键miRNA的表达 在肌瘤（miR-200C和miR-29c）中调节的下调15，16。这些关键miRNA在肌瘤中起关键作用 通过靶向细胞周期调节蛋白的表达和注射（miR-200C），发病机理， ECM（miR-29c）的组成和重塑。此外，最近的报告表明H19 也可以在各种恶性肿瘤中充当MiR-29和MiR-200 Family18-20的赞助商。在这个项目中，我们 确定H19是否可以充当MiR-29/MiR-200家族的赞助商，以及是否可以作为肌瘤中的赞助商 可以降低H19的表达，从而增加miR-29和miR-200的表达 家庭。该项目显然属于我们R01资助的项目的范围，探索了互动 H19与miR-29和miR-200家族。我们假设H19在 Fibroads和Transilast通过抑制MiR-29/miR-200家族的表达 H19的表达。该假设将以两个目的进行检验。 AIM 1：确定LNCRNA H19在肌瘤中的miR-29和miR-200家族的赞助商以及 确定跨层对H19在体外和体内表达的影响。 目标2：确定跨层对miR-29和miR-200家族表达的影响是否介导 由H19。 这些目标的完成不仅会提高我们对长期非编码RNA在中的作用的了解 肌瘤的发病机理和潜在的靶向治疗方法，但也将提供 候选人昆塔尼拉先生的机会学习了许多新的分子和外科技术 并为他为生物医学研究的职业做好准备。