The role of REST in the pathogenesis of uterine fibroids

REST在子宫肌瘤发病机制中的作用

基本信息

批准号：
8596606
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 36.08万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-12 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8596606
关键词：
Benign Binding Brain Cell Proliferation Cells ChIP-seq Clinical Common Neoplasm Data ESR1 gene Environmental Risk Factor Epigenetic Process Estrogens Etiology Exposure to Female Fibroid Tumor Future G-Protein-Coupled Receptors Gene Expression Gene Targeting Genes Genetic Models Genetic Risk Goals Growth Human Hysterectomy In Vitro Knockout Mice Knowledge Laboratories Leiomyoma Ligands Methods Molecular Molecular Target Mus Myometrial Neurons Nuclear PI3K/AKT Pathogenesis Pathway interactions Perinatal Peripheral Pharmaceutical Preparations Phenocopy Phenotype Play Pre-Clinical Model Proteins Quality of life Regulation Repression Repressor Proteins Research Rest Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Testing Tissues Transgenic Organisms Tumor Suppressor Proteins United States Uterine Fibroids Uterus Woman Work cost drug development drug discovery functional loss gain of function human FRAP1 protein in vivo in vivo Model mouse model myometrium neoplastic cell novel overexpression pre-clinical prolactin-releasing peptide promoter public health relevance reproductive therapy development transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Uterine fibroids (leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. Leiomyomas represent the most frequent clinical indication for hysterectomy that often prematurely ends a woman's reproductive capability. In the year 2010, the estimated annual cost of uterine fibroid tumors in the United States was $5.9-34.4 billion. Yet in spite of this, there are currently no approved drugs that can provide effectiv, long-term treatment for these tumors. There is an unmet need to identify molecular targets for the development of therapies to treat uterine fibroids. The long-term goal of our research is to understand the molecular pathogenesis of uterine leiomyomas. Dysregulated PI3K/AKT pathway leading to the activation of mTOR has been suggested to play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas. Further, REST protein is dramatically reduced in leiomyomas. Crucial to the current project, the activation of GPR10, or the loss of REST is suggested to trigger PI3K/AKT signaling and tumor cell proliferation. We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that the loss of REST has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models.

描述（由申请人提供）：子宫肌瘤（平滑肌瘤）是子宫肌层的良性平滑肌细胞（SMC）肿瘤。平滑肌瘤是子宫切除术最常见的临床指征，通常会过早终止女性的生育能力。 2010年，美国子宫肌瘤的年费用估计为5.9-344亿美元。尽管如此，目前还没有批准的药物可以为这些肿瘤提供有效、长期的治疗。确定用于开发治疗子宫肌瘤的疗法的分子靶标的需求尚未得到满足。我们研究的长期目标是了解子宫肌瘤的分子发病机制。导致 mTOR 激活的 PI3K/AKT 通路失调被认为在平滑肌瘤的发病机制中发挥重要作用。我们的初步数据表明，GPR10（一种通常在外周被肿瘤抑制因子 REST/NRSF 沉默的 GPCR）在人类平滑肌瘤中几乎无处不在地过度表达。此外，平滑肌瘤中的 REST 蛋白显着减少。对当前项目至关重要的是，GPR10 的激活或 REST 的丢失被认为会触发 PI3K/AKT 信号传导和肿瘤细胞增殖。我们假设 REST 的缺失导致平滑肌瘤中 GPR10 的表达，并且这种异常的基因表达在功能上促进细胞增殖，从而导致子宫肌瘤的发病机制。当前的项目将确定 REST 缺失对子宫肌瘤发病机制的功能作用。使用体外方法和新颖的体内遗传模型来治疗肌瘤。