Molecular Dissection of Retinoic Acid Function in Leiomyoma Development

描述(由申请人提供)：子宫肌瘤是一种高度常见且有症状的疾病。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着重要作用。尽管有如此戏剧性的症状，子宫肌瘤的病因仍鲜为人知。这种有限的理解已经转化为有限的治疗选择。对于患有子宫肌瘤并希望保持生育能力的女性来说，大手术是目前唯一可用的选择，而且复发并不少见。因此，这些妇女必须在冒着失去妊娠的风险和冒着再次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。更好地了解子宫肌瘤的发展将为医学治疗提供新的靶点，可以将子宫肌瘤对怀孕和一般健康的风险降至最低，同时消除与手术干预相关的风险。构成子宫肌瘤的细胞具有与前体肌细胞和成纤维细胞相似的特征。维甲酸调节多种组织中的细胞分化。我们之前已经证明，构成肌瘤的细胞可以控制分子表达，使维甲酸浓度降至最低。然而，尚不清楚的是，维甲酸暴露会如何改变人类子宫肌瘤的分子和结构表型，以及维甲酸剥夺会对患者匹配的正常子宫肌层产生什么影响。为了解决这个问题，我们从人类组织中产生了永生化细胞系，以测试维甲酸对子宫肌瘤功能作用的假说。我们假设，维甲酸暴露的控制调节了肌瘤特有的分化模式。我们的两个具体目标是：(1)研究维甲酸在人类手术标本和子宫肌瘤和肌层组织培养中的暴露和代谢；(2)利用永生化的子宫肌瘤和肌层细胞系，确定维甲酸对人子宫肌瘤特异性基因分子表达水平的作用。随着这些研究的完成，我们将了解维甲酸途径在肌瘤中的分子变化，并了解维甲酸暴露对分子表达模式的影响。子宫肌瘤和正常子宫肌层之间基因表达的特征差异可以确定可用于治疗的靶点。 公共卫生相关性：子宫肌瘤在育龄妇女中非常普遍，并经常出现症状，导致广泛缺勤，增加雇主成本，每年造成超过80亿美元的社会成本。无法量化的是，由于肌瘤导致的流产，与原本健康的妊娠相关的金钱和情感成本。该提案中概述的研究将提供对肌瘤分化的洞察力，为未来最小化或消除肌瘤及其相关发病率的治疗提供基础工作。

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.