Molecular Dissection of Retinoic Acid Function in Leiomyoma Development

描述（由申请人提供）：子宫平滑肌瘤是高度流行和症状。这些肿瘤在流产、不孕、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，子宫肌瘤的病因是边缘理解。这种有限的理解已经转化为有限的治疗选择。对于患有子宫平滑肌瘤的妇女谁希望保持其生育能力，大手术是唯一的选择，目前可用，复发并不罕见。因此，这些妇女必须在流产风险和再次手术风险之间做出选择，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药物治疗提供新的靶点，可以最大限度地减少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前体肌细胞和成纤维细胞相似的特征。视黄酸调节多种组织中的细胞分化。我们以前已经证明，构成平滑肌瘤的细胞控制分子表达以使视黄酸浓度最小化。然而，目前尚不清楚维甲酸暴露如何改变人类子宫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子宫肌层有何影响。为了解决这个问题，我们已经从人体组织中产生了永生化细胞系，以测试维甲酸对子宫平滑肌瘤的功能作用的假设。我们推测，视黄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）表征人手术标本和平滑肌瘤和子宫肌层组织培养物中视黄酸的暴露和代谢，和（2）使用永生化平滑肌瘤和子宫肌层细胞系确定视黄酸对人子宫平滑肌瘤特异性基因的分子表达水平的作用。通过完成这些研究，我们将了解平滑肌瘤视黄酸途径的分子改变，并了解视黄酸暴露对分子表达模式的影响。子宫平滑肌瘤和正常子宫肌层之间的特征性差异基因表达可以识别可以用于治疗的靶点。 公共卫生相关性：子宫平滑肌瘤在育龄妇女中非常普遍，经常出现症状，导致广泛的缺勤，增加雇主成本，每年超过80亿美元的社会成本。由于子宫肌瘤而导致的健康妊娠流产所带来的金钱和情感代价是不可量化的。本提案中概述的研究将提供对平滑肌瘤分化的深入了解，为未来治疗提供基础，以最大限度地减少或消除平滑肌瘤及其相关的发病率。

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.