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

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.
项目总结/文摘

项目成果

期刊论文数量(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:
    $ 23.69万
  • 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:
    10394958
  • 财政年份:
    2021
  • 资助金额:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 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:
    $ 23.69万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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