Molecular Dissection of Retinoic Acid Function in Leiomyoma Development

视黄酸在平滑肌瘤发展中功能的分子解析

• 批准号: 7639954
• 负责人: William Henry Catherino
• 金额: $ 7.65万
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7639954
• 关键词: Absenteeism; Address; African American; Age; Agonist; Animal Model; Biological Models; Caucasians; Caucasoid Race; Cell Differentiation process; Cell Line; Cells; Characteristics; Clonal Expansion; Critical Pathways; Data; Development; Dissection; Emotional; Enzymes; Etiology; Event; Extracellular Matrix; Fertility; Fibroblasts; Fibroid Tumor; Future; Gene Proteins; Genes; Goals; Growth; Health; Histocompatibility Testing; Human; Human Papillomavirus; Hysterectomy; In Situ; In Vitro; Infertility; Lead; Leiomyoma; Liarozole; Life; Measures; Medical; Menstruation; Metabolism; Molecular; Monitor; Morbidity - disease rate; Muscle Cells; Myometrial; N-methylacetamide-oxotremorine M; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Pelvic Pain; Phenotype; Play; Pregnancy; Pregnancy loss; Premature Labor; Production; Public Health; Recurrence; Regulation; Relative (related person); Repeat Surgery; Retinoids; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specimen; Spontaneous abortion; Symptoms; Testing; Therapeutic; Time; Tissue Microarray; Tissue-Specific Gene Expression; Tissues; Translating; Tretinoin; Urinary Incontinence; Uterine Fibroids; Woman; Work; base; cost; deprivation; dermatopontin; human tissue; immortalized cell; inhibitor/antagonist; insight; mortality; myometrium; novel; novel therapeutics; progenitor; public health relevance; receptor; reproductive; research study; response; therapeutic target; tissue culture; tumor; uterine smooth muscle cell; versican

DESCRIPTION (provided by applicant): Uterine leiomyoma are both highly prevalent and symptomatic. These tumors play a significant role in miscarriage, infertility, preterm labor, heavy menstrual periods, 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 pregnancy loss 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. Cells that make up uterine leiomyomas possess characteristics similar to both the progenitor myocyte and fibroblasts. Retinoic acid regulates cellular differentiation in a wide array of tissues. We have previously demonstrated that cells that make up leiomyomas control molecular expression to minimize retinoic acid concentration. What is unknown, however, is how retinoic acid exposure would alter the molecular and structural phenotype of human uterine leiomyomas, and what retinoic acid deprivation would do to patient-matched normal myometrium. In order to address this question, we have generated immortalized cell lines from human tissue to test hypotheses on the functional role of retinoic acid on uterine leiomyomas. We hypothesize that control of retinoic acid exposure regulates the differentiation pattern unique to leiomyomas. Our two specific aims are: (1) to characterize the exposure and metabolism of retinoic acid in human surgical specimens and tissue cultures of leiomyoma and myometrium, and (2) to determine the role of retinoic acid on molecular expression levels of genes specific to human uterine leiomyomas using immortalized leiomyoma and myometrial cell lines. By the completion of the proposed studies, we will understand the molecular alterations in the retinoic acid pathway of leiomyomas, and understand the impact of retinoic acid exposure on molecular expression patterns. Characterized differential gene expression between leiomyoma and normal myometrium can identify targets that can be exploited therapeutically. PUBLIC HEALTH RELEVANCE: Uterine leiomyomas are highly prevalent and frequently symptomatic in reproductive-aged women, resulting in extensive absenteeism, increased employer cost, and a societal cost of over $8 billion per year. Not as quantifiable, are the associated monetary and emotional costs with the miscarriage of otherwise healthy pregnancies as a result of leiomyomas. The studies outlined in this proposal will provide insight into leiomyoma differentiation, providing the ground-work for future therapies to minimize or eliminate leiomyomas and their associated morbidity.

描述（申请人提供）：子宫平滑肌瘤发病率高，症状明显。这些肿瘤在流产、不孕症、早产、月经过多、盆腔疼痛和尿失禁中起重要作用。尽管如此戏剧性的症状，病因的子宫平滑肌瘤是知之甚少。这种有限的理解已经转化为有限的治疗选择。对于希望保持生育能力的子宫平滑肌瘤患者，大手术是目前唯一可行的选择，而且复发并不罕见。因此，这些妇女必须在冒着流产的风险或冒着重复手术的风险之间做出选择，短期和长期发病率和死亡率的可能性不断增加。更好地了解子宫平滑肌瘤的发展将为医学治疗提供新的靶点，从而最大限度地降低子宫平滑肌瘤对妊娠和一般健康的风险，同时消除与手术干预相关的风险。构成子宫平滑肌瘤的细胞具有与原肌细胞和成纤维细胞相似的特征。维甲酸调节多种组织的细胞分化。我们以前已经证明，构成平滑肌瘤的细胞控制分子表达，以最小化维甲酸浓度。然而，维甲酸暴露如何改变人类子宫平滑肌瘤的分子和结构表型，以及维甲酸剥夺对患者匹配的正常肌层的影响尚不清楚。为了解决这个问题，我们从人体组织中产生了永生细胞系，以测试维甲酸对子宫平滑肌瘤的功能作用的假设。我们假设维甲酸暴露的控制调节平滑肌瘤独特的分化模式。我们的两个具体目标是：(1)表征维甲酸在人类手术标本和平滑肌瘤和子宫内膜组织培养物中的暴露和代谢，(2)利用永生化平滑肌瘤和子宫内膜细胞系确定维甲酸对人类子宫平滑肌瘤特异性基因分子表达水平的作用。通过本研究的完成，我们将了解平滑肌瘤维甲酸通路的分子改变，并了解维甲酸暴露对分子表达模式的影响。平滑肌瘤和正常肌层之间的特征差异基因表达可以确定可用于治疗的靶标。