Role of hormonal state in programming effects of peripubertal stress in females

荷尔蒙状态在女性青春期压力编程效应中的作用

• 批准号: 10178213
• 负责人: Kathleen Elizabeth Morrison
• 金额: $ 19.71万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178213
• 关键词: Address; Adrenal Glands; Adult; Adverse effects; Advisory Committees; Affect; Affective; Allopregnanolone; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Chromatin; Chronic; Clinical; Complex; Corticosterone; Corticotropin-Releasing Hormone; Data; Development; Epigenetic Process; Equilibrium; Estradiol; Female; Foundations; Future; Gene Expression; Genes; Genetic Transcription; Goals; Histones; Hormonal; Hormonal Change; Hypothalamic structure; Immediate-Early Genes; Individual; Institution; Interneurons; Knowledge; Laboratory Research; Late pregnancy; Life; Life Experience; Link; Long-Term Effects; Maternal Behavior; Mental Depression; Mentors; Modeling; Mood Disorders; Mothers; Neurobiology; Neuroendocrinology; Neurons; Neurosecretory Systems; Onset of illness; Pennsylvania; Peripheral; Pharmacology; Phase; Phenotype; Pituitary Gland; Post-Translational Protein Processing; Postpartum Period; Predisposition; Pregnancy; Principal Investigator; Process; Progesterone; Puberty; Research; Research Personnel; Risk; Role; Sexual Dysfunction; Stress; System; Technical Expertise; Time; Training; Training Activity; Universities; Woman; Work; acute stress; base; biological adaptation to stress; career; career development; chromatin modification; design; disorder risk; endophenotype; experience; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; insight; male; mouse model; neuropsychiatric disorder; neurosteroids; novel; paraventricular nucleus; peripartum depression; positive allosteric modulator; postnatal; pregnant; prenatal; programs; promoter; receptor; relating to nervous system; research facility; resilience; response; skills; stressor; success; transcriptome sequencing; vesicular GABA transporter

The training activities, research strategy, and career development activities outlined in this proposal are designed to enable the PI to meet the immediate career goal of gaining experience in epigenetic mechanisms of stress-induced neural reprogramming and neuroendocrinology, and to attain the skills, technical expertise, and career development necessary to succeed in the ultimate career goal of becoming an independent Principle Investigator. This research will help to build a foundation of knowledge for future success in developing translational animal models of stress susceptibility and attain the primary career objective of becoming a successful, independent Principal Investigator, focused on understanding neurobiology and behavior in complex systems that aim to more accurately represent a translationally relevant life experience. The PI is proposing a strategy consisting of coursework, professional development activities, and laboratory research under the guidance of the primary mentor, Dr. Tracy Bale and with guidance from the Advisory Committee. The skills and knowledge gained in the fields of epigenetics and neuroendocrinology are a critical foundation for the proposed work. All of the training will occur at the University of Pennsylvania, a world-renowned research institution with an incredible breadth of state of the art research facilities at my disposal. The proposed research will take place over the course of 5 years, while the training portion will largely take place during Years 1 and 2. Both clinical and animal studies have suggested that females may be more susceptible to stress during puberty. However, the mechanisms underlying these findings are very poorly understood. We have developed a novel peripubertal stress model that enables the examination of both the consequences of peripubertal stress and how that experience interacts with later times of hormonal change, such as pregnancy. In this model, peripubertal stress produces a disruption of the hypothalamic-­pituitary-adrenal (HPA) axis response to acute stress only during pregnancy. Exciting preliminary data implicate long-­term epigenetic changes to the PVN that interact with the unique neuroendocrine milieu of pregnancy to elicit stress dysregulation. Based on these data, we hypothesize that stress dysregulation during pregnancy results from an interaction of pubertal stress reprogramming of the PVN with pregnancy-related increases in allopregnanolone, and that this dysregulation represents an underlying factor that increases disease risk. Three Specific Aims will address this hypothesis by determining the mechanism by which peripuberty stress-induced alterations in the PVN GABA system are due to stable chromatin modifications (Aim 1), how allopregnanolone within the PVN facilitates the blunted HPA axis response in peripubertally stressed females (Aim 2), and the long-term consequences of a subsequent “second hit” stressor experienced during pregnancy (Aim 3).

本建议中概述的培训活动、研究战略和职业发展活动旨在使PI能够实现直接的职业目标，即在应激诱导的神经重编程和神经内分泌学的表观遗传机制方面获得经验，并获得必要的技能、技术专长和职业发展，以成功实现成为独立原则调查员的最终职业目标。这项研究将有助于为未来成功开发应激易感性的翻译动物模型建立知识基础，并实现成为一名成功的、独立的首席研究员的主要职业目标，专注于了解复杂系统中的神经生物学和行为，旨在更准确地代表翻译相关的生活经验。在首席导师特雷西·贝尔博士的指导下和咨询委员会的指导下，国际和平协会提出了一项由课程作业、专业发展活动和实验室研究组成的战略。在表观遗传学和神经内分泌学领域获得的技能和知识是拟议工作的关键基础。所有的培训都将在宾夕法尼亚大学进行，这是一所世界著名的研究机构，拥有令人难以置信的最先进的研究设施供我使用。拟议的研究将在5年内进行，而训练部分将主要在第一年和第二年进行。临床和动物研究都表明，女性在青春期可能更容易受到压力的影响。然而，人们对这些发现背后的机制知之甚少。我们已经开发了一种新的青春期应激模型，该模型能够检查青春期应激的后果，以及这种经历如何与后来的荷尔蒙变化相互作用，如怀孕。在这个模型中，青春期应激只在怀孕期间对急性应激反应产生下丘脑-垂体-肾上腺(HPA)轴的破坏。令人兴奋的初步数据表明，PVN的长期表观遗传变化与怀孕独特的神经内分泌环境相互作用，导致压力失调。基于这些数据，我们假设妊娠期应激失调是青春期应激重编程PVN和妊娠相关的别孕酮增加相互作用的结果，这种失调是增加疾病风险的潜在因素。三个具体的目标将通过确定青春期应激引起的PVN GABA系统中的改变是由于稳定的染色质改变的机制(目标1)，PVN内的别孕酮如何促进青春期应激女性迟钝的HPA轴反应(目标2)，以及随后在怀孕期间经历的第二次打击的压力源的长期后果(目标3)来解决这一假说。