Extra / Intra-cellular Signaling in Novel 3-Dimensional Human Leiomyoma Cultures

新型 3 维人类平滑肌瘤培养物中的细胞外/细胞内信号传导

• 批准号: 8701127
• 负责人: William Henry Catherino
• 金额: $ 18.46万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-13 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701127
• 关键词: 3-Dimensional; Absenteeism; Address; Basic Science; Biological Models; Cell Line; Cells; Cellular Leiomyoma; Characteristics; Data; Deposition; Development; Emotional; Etiology; Event; Extracellular Matrix; Fertility; Fibrosis; Future; Goals; Growth; Health; Human; In Vitro; Infertility; Laboratories; Leiomyoma; Maintenance; Mechanical Stress; Medical; Menorrhagia; Mifepristone; Modeling; Molecular; Morbidity - disease rate; Myometrial; Operative Surgical Procedures; Patients; Pattern; Pelvic Pain; Phenotype; Play; Pregnancy; Premature Labor; Process; Production; Proliferating; Recurrence; Relative (related person); Repeat Surgery; Reproduction; Risk; Role; Signal Pathway; Signal Transduction; Spontaneous abortion; Stress; Surface; Symptoms; Testing; Therapeutic; Time; Translating; Urinary Incontinence; Uterine Fibroids; Woman; Work; aged; biological adaptation to stress; cost; design; effective therapy; extracellular; human disease; immortalized cell; innovation; insight; molecular phenotype; mortality; myometrium; new therapeutic target; novel; novel therapeutics; reproductive; rho; tool; tumor; two-dimensional; unborn child

DESCRIPTION (provided by applicant): Uterine leiomyoma play a significant role in miscarriage, infertility, preterm labor, menorrhagia, pelvic pain, and urinary incontinence. Despite such dramatic symptoms, the etiology of uterine leiomyomas is marginally understood. This limited understanding has translated to limited therapeutic options. For women suffering from uterine leiomyomas who desire to maintain their fertility, major surgery is the only current option available, and recurrence is not uncommon. As a result, these women must choose between risking the demise of an otherwise healthy unborn child or risking repeat surgery, with ever-increasing likelihood of short- and long-term morbidity and mortality. Better understanding of uterine leiomyoma development would provide novel targets for medical therapy that could minimize the risk of uterine leiomyomas on pregnancy and general health while at the same time eliminating the risks associated with surgical intervention. One such medical therapy, mifepristone, decreases tumor size, although the mechanism is unclear. In preliminary studies, we have demonstrated that mifepristone regulated leiomyoma extracellular matrix (ECM) production within the cell. What is unknown, however, is whether mifepristone regulates ECM formation and can stimulate ECM dissolution in leiomyomas, and the mechanism by which ECM regulates the leiomyoma cellular phenotype. In order to address this deficit, we have produced 3-D immortalized cell lines from human leiomyoma and patient-matched myometrium and plan to characterize the impact of mifepristone treatment on ECM formation and degradation. We will also expand upon our findings of aberrant mechanotransduction on ECM production and signaling via the Rho signaling pathway by characterizing ECM production in 3-D leiomyoma cultures relative to 3-D myometrial cultures. Our two specific aims are: (1) to characterize the impact of mifepristone on ECM formation and dissolution on 3-D leiomyoma cultures, and (2) to confirm that perturbations in mechanical stress through formed ECM alter Rho/ERK signaling and increase aberrant ECM formation. By the completion of the proposed studies, we will have characterized the therapeutic impact of a clinically effective therapy (mifepristone) on 3-D leiomyoma ECM, and the impact of Rho signaling on ECM component formation. This project is innovative in that (1) it uses the only model system designed to study ECM, (2) it characterizes a clinically effective therapy, and (3) it uses a human model to study a prevalent human disease.

描述（由申请人提供）：子宫肌瘤在流产、不孕、早产、月经过多、盆腔疼痛和尿失禁中起着重要作用。尽管有如此引人注目的症状，但子宫肌瘤的病因仍知之甚少。这种有限的理解已经转化为有限的治疗选择。对于患有子宫肌瘤且希望维持生育能力的女性来说，大手术是目前唯一的选择，而且复发的情况并不少见。因此，这些妇女必须在健康未出生孩子死亡的风险和重复手术的风险之间做出选择，而短期和长期发病率和死亡率的可能性不断增加。更好地了解子宫肌瘤的发展将为药物治疗提供新的目标，从而最大限度地降低子宫肌瘤对妊娠和总体健康的风险，同时消除与手术干预相关的风险。其中一种药物疗法米非司酮可以减小肿瘤大小，但其机制尚不清楚。在初步研究中，我们已经证明米非司酮调节细胞内平滑肌瘤细胞外基质（ECM）的产生。然而，目前尚不清楚的是，米非司酮是否能调节平滑肌瘤中 ECM 的形成并刺激 ECM 溶解，以及 ECM 调节平滑肌瘤细胞表型的机制。为了解决这一缺陷，我们从人类平滑肌瘤和患者匹配的子宫肌层中产生了 3D 永生化细胞系，并计划表征米非司酮治疗对 ECM 形成和降解的影响。我们还将通过表征 3-D 平滑肌瘤培养物相对于 3-D 子宫肌层培养物中的 ECM 产生来扩展我们通过 Rho 信号通路对 ECM 产生和信号传导的异常机械转导的发现。我们的两个具体目标是：(1) 表征米非司酮对 ECM 形成和 3-D 平滑肌瘤培养物溶解的影响，以及 (2) 确认通过形成的 ECM 产生的机械应力扰动会改变 Rho/ERK 信号传导并增加异常的 ECM 形成。通过完成拟议的研究，我们将表征临床有效疗法（米非司酮）对 3-D 平滑肌瘤 ECM 的治疗影响，以及 Rho 信号对 ECM 成分形成的影响。该项目的创新之处在于（1）它使用唯一设计用于研究 ECM 的模型系统，（2）它描述了一种临床有效的疗法，（3）它使用人体模型来研究人类普遍疾病。