Roles of Nuclear Receptors in Uterine Leiomyoma Proliferation and Fibrosis

核受体在子宫平滑肌瘤增殖和纤维化中的作用

• 批准号: 8934760
• 负责人: DEBABRATA CHAKRAVARTI
• 金额: $ 37.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934760
• 关键词: Affect; Age; Biological Assay; Biology; Cell Proliferation; Cells; Collagen; Collagen Gene; Cyclins; Deposition; Development; Disease; Estrogens; Extracellular Matrix; Family; Fibrosis; Future; Gatekeeping; Genes; Goals; Growth; Health; Human; In Vitro; Instruction; Kidney; Knowledge; Leiomyoma; Ligands; Link; MADH3 gene; Messenger RNA; Molecular; Molecular Profiling; Mus; Myometrial; NR4A1 gene; Nuclear Receptors; Play; Process; Progesterone; Proteins; Public Health; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stem cells; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; United States National Institutes of Health; Uterine Fibroids; Woman; Work; Xenograft Model; Xenograft procedure; base; capsule; cdc Genes; clinically significant; drug development; genome-wide; in vivo; inhibitor/antagonist; innovation; member; myometrium; novel; overexpression; programs; receptor function; reproductive; restoration; therapeutic target; tool; tumorigenesis; uterine smooth muscle cell

Leiomyoma (Uterine fibroids) is a major disease that affects women but remains shockingly understudied with few nonsurgical therapeutic options. Leiomyoma is characterized by excessive deposition of extracellular matrix and enhanced proliferation and tumorigenesis of uterine smooth muscle cells. The roles of estrogen and progesterone and their nuclear receptors (NRs) and transforming growth factor TGFsignaling in leiomyoma are well established. However, the broader role of the nuclear receptor superfamily and their cross talk with TGF signaling pathways in leiomyoma remain as some of the major unanswered questions. The long-term goal of this project is to establish systematically the roles of nuclear receptors (NRs) and their ligands and to understand how TGF signaling is altered in leiomyoma. The goal of this project is to determine the novel roles of NR4A subfamily members, including NR4A1 (NGF1B), NR4A2 (NURR1), and NR4A3 (NOR1) in leiomyoma. We performed expression profiling of leiomyoma tissues and adjacent normal myometrium for all 48 human NRs and demonstrated severe deficiency of the NR4A subfamily members, including NR4A1 (NGF1B), NR4A2 (NURR1), and NR4A3 (NOR1), in leiomyoma. Our preliminary results show that NR4A functions by regulating expression of key profibrotic factors such as TGF3 and SMAD3 and key extracellular matrix components such as collagen 1A1. Furthermore, NR4As regulate proliferation of leiomyoma primary smooth muscle cells. We hypothesize that the NR4A family of nuclear receptors plays critical and integrative roles involving TGF and SMAD signaling in leiomyoma development by regulating key proliferation and profibrotic genes. The specific aims are: Specific Aim 1: Determine how NR4A and TGF /SMAD signaling pathways interact to regulate pro-fibrotic genes in leiomyoma. Specific Aim 2: Determine the roles of NR4As and their selective modulators in leiomyoma cell proliferation in vitro and tumorigenesis in vivo. The proposed aims will advance our knowledge of this highly prevalent public health challenge for which treatment options are currently limited at best. The proposed work is scientifically, translationally, and clinically significant because it provides a new perspective on and better understanding of the mechanisms underlying leiomyoma development and opens up possibilities for identifying additional therapeutic targets and strategies. It is innovative because it represents the first systematic exploration of previously unrealized roles of the NR4A nuclear receptor family in leiomyoma biology.

平滑肌瘤(子宫肌瘤)是一种影响女性的主要疾病，但仍未得到足够的研究 几乎没有非手术治疗的选择。平滑肌瘤的特征是细胞外过度沉积。 基质和增强子宫平滑肌细胞的增殖和肿瘤发生。雌激素和雌激素的作用 孕酮及其核受体与转化生长因子转化生长因子信号转导 平滑肌瘤是一种常见的疾病。然而，核受体超家族及其杂交的更广泛的作用 与转化生长因子信号通路在子宫肌瘤中的对话仍然是一些主要的悬而未决的问题。这个 该项目的长期目标是系统地确定核受体(NRs)及其受体的作用 并了解转化生长因子信号在肌瘤中是如何改变的。这个项目的目标是确定 NR4A亚家族成员的新角色，包括NR4A1(NGF1B)、NR4A2(NURR1)和NR4A3 (Nor1)在肌瘤中。我们对子宫肌瘤组织和邻近正常组织进行了表达谱分析。 所有48个人类NRS的子宫肌层，并显示NR4A亚家族成员严重缺乏， 包括NR4A1(NGF1B)、NR4A2(NURR1)和NR4A3(Nor1)。我们的初步结果显示 NR4A通过调节转化生长因子3、Smad3和Key等关键促纤维化因子的表达发挥作用 细胞外基质成分，如胶原蛋白1A1。此外，NR4A还控制着细胞的增殖 平滑肌瘤原代平滑肌细胞。我们假设NR4A家族的核受体在 转化生长因子和SmadD信号调控Key在子宫肌瘤发生中的重要作用 增殖和促纤维化基因。具体目标是：具体目标1：确定NR4A和转化生长因子 /SMAD信号通路相互作用，调节子宫肌瘤中的促纤维化基因。具体目标2：确定 NR4As及其选择性调节因子在子宫肌瘤细胞体外增殖和体内成瘤中的作用 拟议的目标将增进我们对这一高度普遍的公共卫生挑战的了解 目前，治疗选择充其量也是有限的。建议的工作是科学的、翻译的和临床的。 意义重大，因为它提供了一个新的视角，并更好地理解了潜在的机制 此外，我们还研究了平滑肌瘤的发展，并为确定其他治疗靶点和策略开辟了可能性。 它具有创新性，因为它代表了对以前未实现的NR4A角色的首次系统探索 肌瘤生物学中的核受体家族。