Novel regulation of early follicle formation
早期卵泡形成的新调控
基本信息
- 批准号:10207699
- 负责人:
- 金额:$ 31.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ACVR1 geneAddressAffectBMP2 geneBasic ScienceBioinformaticsBiologicalBiological ModelsCadherinsCandidate Disease GeneCell AdhesionCell CommunicationCoupledDefectDevelopmentDiagnosisEpithelialEstradiolEventExperimental ModelsExposure toFOXL2 geneFemaleFertilityFollicle Stimulating Hormone ReceptorGDF9 geneGenesGerm CellsGoalsHamstersHumanIn VitroInfertilityLeadLifeLigandsLightMammalsMediatingMeiosisMesenchymalMolecularMutationOocytesOvarianOvarian DiseasesOvarian FollicleOvarian hormoneOvaryPathway interactionsPremature Ovarian FailurePrimordial FollicleProbabilityProcessRecombinantsRegulationRoleSmall Interfering RNASomatic CellSystemTransitional EpitheliumTurner&aposs SyndromeUndifferentiatedValidationWomanbasebone morphogenic proteincell assemblydifferential expressionfetalfolliculogenesisgranulosa cellimprovedin vivoknock-downnovelovarian dysfunctionparacrinereceptorreproductivesmall hairpin RNAsmall molecule inhibitortranscriptome sequencingvascular endothelial cadherin-2
项目摘要
The fundamental mechanism responsible for the transition of undifferentiated somatic cells (SCs) into gran-
ulosa cells (GCs) during primordial follicle (PF) formation is poorly understood. Women with premature ovarian
failure (POF), Turner Syndrome or inactivating mutation of FSH receptor are infertile and have defective and
non-growing PFs. Therefore, the basic research on PF formation is necessary to understand the molecular basis
of normal and defective folliculogenesis. We present compelling evidence that (1) bone morphogenic protein 2
(BMP2, a SC-derived ligand), GDF9 (an oocyte-derived ligand) and estradiol-17 (E2, an ovarian hormone) inter-
act to promote PF formation in fetal ovaries, (2) the paracrine actions of GDF9 require BMP2 priming of SCs,
and (3) inactivation of cadherin 2 (CDH2) interferes with PF formation.19 These important findings lead us to
hypothesize that BMP2 and GDF9 spatio-temporally promote the transition of SCs into GCs and their
assembly with the oocytes. E2 modulates the actions of BMP2 by upregulating the synthesis of BMP2
ligand and receptors. The specific aims (Fig. 1) are (1) Determine the mechanism of BMP2-mediated pri-
mordial follicle (PF) formation. The objectives are, (1) To determine if BMP2 regulates the transition of SCs
into GCs, (2) To determine if GDF9 action is required for or facilitates the transition of SCs to GCs, and (3) To
determine if GDF9 facilitates oocyte-granulosa cell adhesion and assembly. We will knockdown BMP2 or GDF9
expression or block their actions or alter ALK2/3 activities in E15 hamster ovaries in vitro by small molecule
inhibitors or shRNA. (2) Determine if estradiol-17 (E2) regulates BMP2-ALK3/ ALK2 system. The objective
is to determine if E2 affects PF formation by regulating the expression and action of BMP2. We will knockdown
or block BMP2 action or alter ALK2/3 activities by small molecule inhibitors or shRNA in hamster fetal ovaries,
and in ovary recombinants to determine the mechanism of E2-induced SC to GC transition. (3) Analysis of gene
networks affected by BMP2 or GDF9 during PF formation. The objective is to identify and analyze gene
networks and corresponding pathways in SCs that are targeted by BMP2 or GDF9 during PF formation. We will
use RNAseq analysis to determine differentially expressed genes (DEGs) in SCs of ovaries exposed to BMP2
or GDF9. High stringency cut off along with bioinformatics analysis will be used to select candidate genes for
biological validation and will be prioritized based on their role in mesenchymal-epithelial transition (MET), in
follicular development and functions, and the probability of their defects causing ovarian dysfunction. Biological
validation will be accomplished using approaches outlined in Aim 1. This study will provide novel information to
understand the basic mechanism responsible for the transition of undifferentiated SCs into GCs during PF for-
mation, and may shed light to better understand the molecular basis of defects in PF formation.
导致未分化的体细胞(SC)过渡到粒度的基本机制
原始卵泡(PF)形成期间的Ulosa细胞(GC)的理解很少。卵巢过早的妇女
FSH受体的失败(POF),Turner综合征或灭活突变是不育的,并且有缺陷
非生长的PFS。因此,关于PF形成的基础研究对于了解分子基础是必要的
正常和缺陷的卵泡发生。我们提供了令人信服的证据,表明(1)骨形态发生蛋白2
(BMP2,SC衍生的配体),GDF9(卵母细胞衍生的配体)和Estradiol-17(E2,卵巢激素)间
促进胎儿卵巢中PF形成的作用,(2)GDF9的旁分泌作用需要SC的BMP2启动,
(3)cadherin 2(CDH2)灭活PF形成。19这些重要发现使我们进入
假设BMP2和GDF9时空暂时性地促进了SCS及其GC的过渡
带有卵母细胞组装。 E2通过上调BMP2的合成来调节BMP2的作用
配体和受体。具体目的(图1)是(1)确定BMP2介导的原理的机理
膜片卵泡(PF)形成。目标是(1)确定BMP2是否调节SC的过渡
进入GC,(2)确定是否需要或促进SC向GCS的过渡以及(3)至
确定GDF9是否促进了卵母细胞颗粒细胞的粘附和组装。我们将敲除BMP2或GDF9
在体外表达或阻止其作用或改变E15仓鼠卵巢中的ALK2/3活性。
抑制剂或shRNA。 (2)确定雌二醇17(E2)是否调节BMP2-Alk3/ Alk2系统。目标
是通过调节BMP2的表达和作用来确定E2是否影响PF的形成。我们将击倒
或阻止BMP2作用或改变仓鼠胎儿卵巢中的小分子抑制剂或shRNA的ALK2/3活性,
并在卵巢重组中确定E2诱导的SC到GC转变的机理。 (3)基因分析
PF组中受BMP2或GDF9影响的网络。目的是识别和分析基因
在PF形成过程中,BMP2或GDF9靶向的SC中的网络和相应途径。我们将
使用RNASEQ分析确定暴露于BMP2的卵巢SC中差异表达的基因(DEG)
或GDF9。与生物信息学分析一起切断的高严格度将用于选择候选基因
生物学验证,并将根据其在间充质 - 上皮过渡(MET)中的作用而优先级
卵泡发育和功能,以及它们的缺陷概率引起了卵巢功能障碍。生物
将使用AIM 1中概述的方法来实现验证。本研究将提供新的信息
了解导致未分化的SC在PF期间转变为GC的基本机制
物质,可能会发光以更好地理解PF形成中缺陷的分子基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SHYAMAL K. ROY其他文献
SHYAMAL K. ROY的其他文献
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{{ truncateString('SHYAMAL K. ROY', 18)}}的其他基金
Molecular Biology, Biochemistry and Histology Core
分子生物学、生物化学和组织学核心
- 批准号:
7750840 - 财政年份:2009
- 资助金额:
$ 31.76万 - 项目类别:
CORE--MOLECULAR BIOLOGY, BIOCHEMISTRY & HISTOLOGY
核心--分子生物学、生物化学
- 批准号:
6928293 - 财政年份:2004
- 资助金额:
$ 31.76万 - 项目类别:
CORE--MOLECULAR BIOLOGY, BIOCHEMISTRY AND HISTOLOGY
核心--分子生物学、生物化学和组织学
- 批准号:
6606560 - 财政年份:2002
- 资助金额:
$ 31.76万 - 项目类别:
FOLLICULAR MORPHOGENESIS DURING PERINATAL DEVELOPMENT
围产期发育期间的卵泡形态发生
- 批准号:
6637057 - 财政年份:2001
- 资助金额:
$ 31.76万 - 项目类别:
FOLLICULAR MORPHOGENESIS DURING PERINATAL DEVELOPMENT
围产期发育期间的卵泡形态发生
- 批准号:
6740919 - 财政年份:2001
- 资助金额:
$ 31.76万 - 项目类别:
CORE--MOLECULAR BIOLOGY, BIOCHEMISTRY AND HISTOLOGY
核心--分子生物学、生物化学和组织学
- 批准号:
6457669 - 财政年份:2001
- 资助金额:
$ 31.76万 - 项目类别:
Follicular morphogenesis during perinatal development
围产期发育过程中的卵泡形态发生
- 批准号:
7367993 - 财政年份:2001
- 资助金额:
$ 31.76万 - 项目类别:
Follicular morphogenesis during perinatal development
围产期发育过程中的卵泡形态发生
- 批准号:
8091316 - 财政年份:2001
- 资助金额:
$ 31.76万 - 项目类别:
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