Interrogating the Role of HSF1 in Ovarian Stress

探究 HSF1 在卵巢应激中的作用

基本信息

批准号：
10536083
负责人：
Mariko Foecke
金额：
$ 4.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-10-01 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536083
关键词：
3-Dimensional Adult Affect Agonist Architecture Behavior Behavioral Binding Blood Circulation California Cell Nucleus Cells Chromosomes Cognitive deficits Competence Development Dexamethasone Drosophila genus Embryo Embryonic Development Ensure Environmental Risk Factor Exposure to Fellowship Fertility Fetal Development Generations Genetic Genetic Transcription Genetic Variation Germ Cells Glucocorticoid Receptor Glucocorticoids Goals Growth Harvest Health Heat-Shock Response Homeostasis Hormones Human Immune Impairment In Vitro Laboratories Lead Mammals Maps Measures Mediating Meiosis Memory Mentorship Metabolic Molecular Mus National Research Service Awards Nematoda Oocytes Ovarian Ovary Pharmacology Phenocopy Physiological Play Ploidies Population Pregnancy Premature Birth Process Prophase Proteins Receptor Inhibition Receptor Signaling Reproductive Biology Research Role San Francisco Signal Transduction Stress System Testing Three-Dimensional Imaging Time Training Transcript Universities Vulnerable Populations Woman Work career conditional knockout experience experimental study fetal heat-shock factor 1 high risk hypothalamic-pituitary-adrenal axis improved in vivo in vivo Model lung maturation maternal stress mouse model negative affect neurodevelopment pre-doctoral pregnant protein expression proteostasis pup reproductive reproductive fitness response social health determinants social implication socioeconomics spatiotemporal steroid hormone theories transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT It has long been known that physiological stress during gestation can lead to the alteration of stress and metabolic responses over multiple generations. Such information must be transmitted through the germline; however, the mechanistic effects of physiological stress on the germline and, more broadly, whether stress- related changes occur at the level of the germ cells themselves remain unexplored. The maternal hypothalamic- pituitary-adrenal axis is activated upon gestational stress and its downstream effectors are glucocorticoids, a class of steroid hormones, which are released into the bloodstream then bind to the ubiquitously expressed Glucocorticoid Receptor (GR). While stress-induced levels of glucocorticoids are known to impair oocyte competence in adult women, their impact on the fetal oocyte remains largely unexplored. Interestingly, GR has been shown to downregulate the activity of Heat Shock Factor 1 (HSF1). While HSF1 is well characterized for its role in proteostasis, it is also known to regulate chromosome architecture in the oocyte during meiosis. This proposal will investigate how oocyte intrinsic HSF1 activity and maternal gestational stress influence fetal oocyte development. By using genetic mouse models, in vivo models of increased GR activity, whole ovary clearing, three-dimensional imaging, and quantitative analysis, this proposal will (1) establish a comprehensive, three-dimensional spatiotemporal map of HSF1 expression, localization, and activity in the fetal ovary and test whether HSF1 plays a germ cell-intrinsic role in embryonic meiosis and (2) identify the relationship between GR and Hsf1 in the fetal oocyte and the consequences for both embryonic meiosis and oocyte growth and maturation. Improving our limited understanding of the long-term consequences of global increased GR activity on the developing germline is crucial as the potent pharmacological agonist of GR, dexamethasone, is routinely administered during pregnancy to stimulate lung maturation when premature birth is a concern. Additionally, elucidating the mechanistic effects of physiological stress in the oocyte will support our understanding of the consequences for vulnerable populations who have a higher risk of exposure to stress- inducing environmental and socioeconomic conditions. To successfully complete the work outlined in this F31 proposal and to achieve my career goals, I have chosen to perform the proposed work in the laboratory of my Sponsor, Dr. Diana Laird, at the University of California, San Francisco. The complementary expertise of my Co-Sponsor, Dr. Marco Conti, and Collaborator, Dr. Aditi Bhargava, as well as the support provided by this F31 Fellowship assure I will receive the technical training and mentorship to complete my pre-doctoral research and contribute to the field of reproductive biology.

项目概要/摘要众所周知，妊娠期间的生理应激会导致应激和应激状态的改变。多代的代谢反应。此类信息必须通过种系传递；然而，生理应激对种系的机械影响，以及更广泛地说，应激是否生殖细胞本身水平发生的相关变化仍未被探索。母体下丘脑—— 垂体-肾上腺轴在妊娠应激时被激活，其下游效应器是糖皮质激素，一类类固醇激素，释放到血液中，然后与普遍表达的糖皮质激素受体（GR）。虽然已知压力诱导的糖皮质激素水平会损害卵母细胞尽管它们对成年女性的能力有影响，但它们对胎儿卵母细胞的影响在很大程度上仍未得到探索。有趣的是，GR 有已被证明可以下调热休克因子 1 (HSF1) 的活性。虽然 HSF1 的特点是除了其在蛋白质稳态中的作用，它还可以在减数分裂过程中调节卵母细胞的染色体结构。这该提案将研究卵母细胞固有的 HSF1 活性和母亲妊娠应激如何影响胎儿卵母细胞的发育。通过使用遗传小鼠模型，GR 活性增加的体内模型，卵巢透明化、三维成像和定量分析，该提案将（1）建立一个胎儿中 HSF1 表达、定位和活性的全面三维时空图卵巢并测试 HSF1 是否在胚胎减数分裂中发挥生殖细胞固有的作用，并且 (2) 确定其中的关系胎儿卵母细胞中 GR 和 Hsf1 之间的关系及其对胚胎减数分裂和卵母细胞生长的影响和成熟。提高我们对全球遗传资源增加的长期后果的有限了解对发育中种系的活性至关重要，因为 GR 的有效药理学激动剂地塞米松当担心早产时，在怀孕期间常规施用以刺激肺部成熟。此外，阐明卵母细胞生理应激的机制效应将支持我们的研究了解对承受压力风险较高的弱势群体的后果诱发环境和社会经济条件。为了成功完成本 F31 提案中概述的工作并实现我的职业目标，我选择在我的资助者戴安娜·莱尔德博士（加州大学）的实验室中进行拟议的工作，旧金山。我的共同发起人 Marco Conti 博士和合作者 Aditi 博士的互补专业知识 Bhargava 以及 F31 奖学金提供的支持确保我将接受技术培训和指导我完成博士前研究并为生殖生物学领域做出贡献。