Transcriptomic and epigenomic basis for reproductive dysfunction during stress
应激期间生殖功能障碍的转录组和表观基因组基础
基本信息
- 批准号:10394958
- 负责人:
- 金额:$ 19.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAmenorrheaAnimal ModelBindingBinding SitesBiological AssayBiomedical ResearchBreast Cancer CellCardiac healthCell NucleusCellsChIP-seqChromatinCoupledCuesDataDevelopmentDiestrusEmploymentEpigenetic ProcessEstradiolEstrogen ReceptorsEstrogensExposure toFemaleFertilityFunctional disorderFutureGene ExpressionGenerationsGenetic TranscriptionGlucocorticoid ReceptorGlucocorticoidsGonadal Steroid HormonesGonadotropin Hormone Releasing HormoneGonadotropinsHomeostasisHormone secretionHormonesHypothalamic structureImpairmentImplantInfertilityKISS1 geneKnowledgeLaboratoriesLuteinizing HormoneMapsMediatingMenstruation DisturbancesMethodsMolecularMusNeuronsNeurosecretory SystemsNuclear EnvelopeOvarianOvarian CyclesPatternPhysiologic pulsePhysiologicalPopulationProductionProtocols documentationReagentRegulationReproductionResearchResearch PersonnelResourcesSignal TransductionSteroidsStressTalentsTechnologyTestingTransgenic OrganismsTransposaseWomanWomen&aposs HealthWorkbasebone healthbrain healthcell typecholesterol controlchromatin immunoprecipitationdruggable targetenv Gene Productsepigenomeepigenomicsfallsgenome-wideglucocorticoid-induced orphan receptorhigh rewardhigh riskinnovationinterestmaleneuromechanismneuroregulationnext generation sequencingnovelpreventreceptorreceptor bindingreproductivereproductive system disorderresponsestressortooltranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary/Abstract
Stress is considered a major factor in the development of menstrual cycle disorders, amenorrhea, and infertility,
affecting 25% of reproductive age women. To date, the neuroendocrine causes of stress-induced infertility are
not completely understood. Enhanced secretion of glucocorticoids (CORT) is a common and critical response to
all stressors. We demonstrated that a stress level of CORT disrupts the ovulatory cycle of female mice via
suppression of kisspeptin (Kiss1) neurons located in both arcuate (ARCKiss1) and anteroventral periventricular
(AVPVKiss1) nuclei, which are essential components of the neural control of reproduction. The effect of CORT
depends on ovarian steroid milieu. Specifically, low diestrus levels of estradiol enable CORT to impair ARCKiss1
control of luteinizing hormone (LH) pulses and high surge estradiol levels enable CORT to prevent AVPVKiss1
neuronal activation of the LH secretion. Receptors for estrogen and glucocorticoid receptors (GR) are both in
Kiss1 neurons; however, the interaction of GR and ER to modulate the transcriptomic and epigenomic landscape
within ARCKiss1 or AVPVKiss1 neurons to suppress LH secretion remains unclear. This proposal employs a cutting-
edge method to capture and isolate Kiss1 cells from heterogeneous ARC or AVPV cell populations. The Isolation
of Nuclei Tagged in specific Cell-Types (INTACT) protocol employs expression of a tagged nuclear envelope
protein (Sun1) only in Kiss1 cells (i.e. Cre-dependent) for rapid isolation of tagged nuclei for downstream
transcriptomic and epigenomic sequencing. Aim 1 will test the hypothesis that estradiol enables CORT to alter
the transcriptome of Kiss1 neurons, facilitating suppressed ARCKiss1 and AVPVKiss1 neuronal activity and lowered
pulsatile and surge-type LH secretion, respectively. Mice will be OVX and receive diestrus-like (ARCKiss1) or
surge-level replacement (AVPVKiss1) of estradiol and treated with CORT or cholesterol (control), and the
transcriptome of INTACT-isolated Kiss cells will be evaluated by RNA-sequencing. Aim 2 will test the hypothesis
that estradiol drives changes of the chromatin landscape of ARCKiss1 and AVPVKiss1 neurons allowing GR to bind
and alter the neuronal transcriptome. INTACT will be coupled with: (2.1) Assay for Transposase-Accessible
Chromatin (ATAC-seq) to evaluate the epigenome for open chromatin in mediated by estradiol and CORT and
(2.2) chromatin immunoprecipitation (ChIP-seq) to directly map the genome-wide binding profile of GR in
ARCKiss1 and AVPVKiss1 cells to test the hypothesis that GR binding sites are made accessible by estradiol
(hormone treatments described in Aim 1). Successful completion of this proposal will significantly increase our
knowledge of intracellular mechanisms that govern the physiologic responsiveness of Kiss1 neurons, which will
be tested in subsequent work and may identify druggable targets to influence the management of reproductive
disorders resulting from impaired central regulation. This application falls within the scope of the high risk-high
reward mechanism and will result in novel reagents that will impact biomedical research. All methods, hormone
treatments and the animal model (Kiss1-CrexSun1-GFP) are available within this investigative team.
项目概要/摘要
压力被认为是导致月经周期紊乱、闭经和不孕的主要因素,
影响25%的育龄妇女。迄今为止,应激性不孕症的神经内分泌原因是
没有完全理解。糖皮质激素 (CORT) 分泌增强是一种常见且关键的反应
所有压力源。我们证明,CORT 的应激水平会通过以下方式扰乱雌性小鼠的排卵周期:
抑制位于弓状 (ARCKiss1) 和前腹侧脑室周围的 Kisspeptin (Kiss1) 神经元
(AVPVKiss1) 细胞核,是生殖神经控制的重要组成部分。 CORT的作用
取决于卵巢类固醇环境。具体来说,低发情间期水平的雌二醇使 CORT 能够损害 ARCKiss1
控制黄体生成素 (LH) 脉冲和高雌二醇水平使 CORT 能够预防 AVPVKiss1
LH 分泌的神经元激活。雌激素受体和糖皮质激素受体 (GR) 均位于
Kiss1神经元;然而,GR 和 ER 的相互作用调节转录组和表观基因组景观
ARCKiss1 或 AVPVKiss1 神经元内抑制 LH 分泌的作用尚不清楚。该提案采用了切割-
边缘方法从异质 ARC 或 AVPV 细胞群中捕获和分离 Kiss1 细胞。隔离
特定细胞类型中标记的细胞核 (INTACT) 方案采用标记核膜的表达
蛋白质 (Sun1) 仅存在于 Kiss1 细胞中(即 Cre 依赖性),用于快速分离下游标记的细胞核
转录组和表观基因组测序。目标 1 将检验雌二醇使 CORT 改变的假设
Kiss1 神经元的转录组,促进 ARCKiss1 和 AVPVKiss1 神经元活动受到抑制并降低
分别为脉冲型和激增型 LH 分泌。小鼠将是 OVX 并接受发情间期样 (ARCKiss1) 或
雌二醇的激增水平替代(AVPVKiss1)并用 CORT 或胆固醇(对照)治疗,以及
完整分离的 Kiss 细胞的转录组将通过 RNA 测序进行评估。目标 2 将检验假设
雌二醇驱动 ARCKiss1 和 AVPVKiss1 神经元染色质景观的变化,从而允许 GR 结合
并改变神经元转录组。 INTACT 将与:(2.1) 转座酶可及性检测相结合
染色质 (ATAC-seq) 用于评估雌二醇和 CORT 介导的开放染色质的表观基因组
(2.2) 染色质免疫沉淀 (ChIP-seq) 直接绘制 GR 的全基因组结合谱
ARCKiss1 和 AVPVKiss1 细胞用于测试雌二醇可接近 GR 结合位点的假设
(目标 1 中描述的激素治疗)。该提案的成功完成将显着提高我们的
了解控制 Kiss1 神经元生理反应的细胞内机制,这将
在后续工作中进行测试,并可能确定可影响生殖管理的药物靶点
中枢调节功能受损导致的疾病。该应用属于高风险高风险范围
奖励机制并将产生影响生物医学研究的新型试剂。所有方法,激素
该研究团队提供了治疗方法和动物模型(Kiss1-CrexSun1-GFP)。
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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KELLIE Breen Church其他文献
KELLIE Breen Church的其他文献
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{{ truncateString('KELLIE Breen Church', 18)}}的其他基金
FASEB SRC: The Mechanisms of Allostasis Conference: Stressed or Stressed Out
FASEB SRC:动态平衡机制会议:压力还是压力过大
- 批准号:
10537130 - 财政年份:2022
- 资助金额:
$ 19.75万 - 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
- 批准号:
10298510 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
- 批准号:
10684307 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
应激期间生殖功能障碍的转录组和表观基因组基础
- 批准号:
10195913 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
- 批准号:
10488654 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
- 批准号:
9325553 - 财政年份:2016
- 资助金额:
$ 19.75万 - 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
- 批准号:
9895818 - 财政年份:2016
- 资助金额:
$ 19.75万 - 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
- 批准号:
9177432 - 财政年份:2016
- 资助金额:
$ 19.75万 - 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
- 批准号:
7893551 - 财政年份:2010
- 资助金额:
$ 19.75万 - 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
- 批准号:
8810674 - 财政年份:2010
- 资助金额:
$ 19.75万 - 项目类别:
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