Roles of Nuclear Receptors in Uterine Leiomyoma Proliferation and Fibrosis

平滑肌瘤（子宫肌瘤）是一种影响女性的主要疾病，但仍然令人震惊地研究不足， 一些非手术治疗选择。平滑肌瘤的特征是细胞外基质过度沉积， 基质和子宫平滑肌细胞的增殖和肿瘤发生增强。雌激素和 孕酮及其核受体（NRs）和转化生长因子β 1-TGF β 1-信号通路在 平滑肌瘤是很好建立。然而，核受体超家族的更广泛作用及其交叉 TGF β 1信号通路在平滑肌瘤中的作用仍是一些尚未解决的问题。的 该项目的长期目标是系统地建立核受体（NRs）及其 配体，并了解TGF β信号是如何改变平滑肌瘤。这个项目的目标是确定 NR 4A亚家族成员的新作用，包括NR 4A 1（NGF 1B），NR 4A 2（NGF 1 R1）和NR 4A 3 （NOR 1）在平滑肌瘤中的表达。我们对平滑肌瘤组织和邻近正常组织进行了表达谱分析， 所有48个人NR的子宫肌层，并证明NR 4A亚家族成员的严重缺乏， 包括NR 4A 1（NGF 1B）、NR 4A 2（NGF 1 R1）和NR 4A 3（NOR 1）。我们的初步结果表明 NR 4A通过调节关键促纤维化因子如TGF β 3和SMAD 3的表达发挥作用， 细胞外基质成分如胶原1A 1。此外，NR 4A调节细胞增殖， 平滑肌瘤原代平滑肌细胞。我们假设NR 4A家族的核受体发挥作用， TGF β 1和SMAD信号通过调节关键蛋白在平滑肌瘤发展中的关键和整合作用 增殖和促纤维化基因。具体目标1：确定NR 4A和TGF β 1是如何通过 /SMAD信号通路相互作用以调节平滑肌瘤中的促纤维化基因。具体目标2：确定 NR 4As及其选择性调节剂在平滑肌瘤细胞体外增殖和体内成瘤中的作用 拟议的目标将促进我们对这一高度普遍的公共卫生挑战的认识， 目前的治疗选择充其量是有限的。所提出的工作具有科学性、实用性和临床性 重要的是，它提供了一个新的视角，更好地了解其背后的机制， 平滑肌瘤的发展，并开辟了可能性，以确定额外的治疗目标和战略。 它是创新的，因为它代表了NR 4A以前未实现的作用的第一次系统性探索 核受体家族在平滑肌瘤生物学中的作用。

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.