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

基本信息

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
项目类别：
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

项目摘要

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).

该提案中概述的培训活动，研究策略和职业发展活动旨在使PI能够实现在压力引起的神经元重编程和神经内分泌学的表观遗传机制方面获得经验的直接职业目标，并实现了成为独立公主研究员的最终职业生涯目标所必需的技能，技术专业知识以及实现最终职业生涯的所必需的职业发展。这项研究将有助于建立知识的基础，以开发压力敏感性的转化动物模型，并实现成为成功，独立的首席研究人员的主要职业目标，专注于理解复杂系统中的神经生物学和行为，旨在更准确地代表转化相关的生活体验。 PI在主要导师Tracy Bale博士的指导下以及在咨询委员会的指导下，提出了一项由课程，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，这是一家世界知名的研究机构，我可以掌握真实的研究设施。拟议的研究将在5年的时间内进行，而培训部分将在1年和2年内进行。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。但是，这些发现的基础机制知之甚少。我们已经开发了一种新型的周围应力模型，该模型可以检查围绕骨的压力的后果以及这种体验如何与诸如妊娠等激素变化的以后时间相互作用。在该模型中，peripiuberberbertal应激会导致下丘脑 - 垂体 - 肾上腺（HPA）轴对急性应激的反应仅在怀孕期间。令人兴奋的初步数据暗示了与PVN与独特的神经内分泌环境相互作用的长期表观遗传变化，以引起压力失调。基于这些数据，我们假设怀孕期间的压力失调是由于PVN的青春期应力重编程与Allopregnanolone的妊娠相关增加的相互作用，而这种失调代表了增加疾病风险的潜在因素。 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 （目标3）。