Roles of Nuclear Receptors in Uterine Leiomyoma Proliferation and Fibrosis
Roles of Nuclear Receptors in Uterine Leiomyoma Proliferation and Fibrosis
批准号:
9162083
负责人:
DEBABRATA CHAKRAVARTI
金额:
$36.1万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
未结题
起止时间:
2009-08-15 至
关键词:
AffectAgeBiological AssayBiologyCell ProliferationCellsCollagenCollagen GeneCyclinsDepositionDevelopmentDiseaseEstrogensExtracellular MatrixFamilyFibrosisFutureGatekeepingGenesGoalsGrowthHealthHumanIn VitroInstructionKidneyKnowledgeLeiomyomaLigandsLinkMADH3 geneMessenger RNAMolecularMolecular ProfilingMusMyometrialNR4A1 geneNuclear ReceptorsPlayProcessProgesteroneProteinsPublic HealthPublishingRegulationResearchRoleSignal PathwaySignal TransductionSmooth Muscle MyocytesStem cellsSystemTestingTherapeuticTherapeutic InterventionTissuesTransforming Growth Factor betaTransforming Growth FactorsUnited States National Institutes of HealthUterine FibroidsWomanWorkXenograft ModelXenograft procedurebasecapsulecdc Genesclinically significantdrug developmentgenome-widein vivoinhibitor/antagonistinnovationmembermyometriumnoveloverexpressionprogramsreceptor functionreproductiverestorationtargeted treatmenttherapeutic targettooltumorigenesisuterine smooth muscle cell
中文摘要
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。
英文摘要
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 TGFsignaling 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 TGF3 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.
期刊论文(0)
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会议论文
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依托单位:
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