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

本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 能够实现获得应激诱导神经重编程和神经内分泌学表观遗传机制经验的近期职业目标，并获得成功实现成为独立首席研究员的最终职业目标所需的技能、技术专长和职业发展。这项研究将有助于为未来成功开发应激易感性转化动物模型奠定知识基础，并实现成为一名成功的独立首席研究员的主要职业目标，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经历。 PI 在主要导师 Tracy Bale 博士的指导和咨询委员会的指导下提出了一项战略，包括课程作业、专业发展活动和实验室研究。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。拟议的研究将持续 5 年，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。然而，人们对这些发现背后的机制知之甚少。我们开发了一种新颖的围青春期压力模型，可以检查青春期围压力的后果以及这种经历如何与后期荷尔蒙变化（例如怀孕）相互作用。在该模型中，青春期前后的应激仅会扰乱怀孕期间下丘脑-垂体-肾上腺（HPA）轴对急性应激的反应。令人兴奋的初步数据表明 PVN 的长期表观遗传变化与妊娠期独特的神经内分泌环境相互作用，引发应激失调。基于这些数据，我们假设妊娠期间的压力失调是由 PVN 的青春期压力重编程与妊娠相关的四氢孕酮增加相互作用造成的，并且这种失调是增加疾病风险的潜在因素。三个具体目标将通过确定青春期压力引起的 PVN GABA 系统变化归因于稳定染色质修饰的机制（目标 1）、PVN 内的四氢孕酮如何促进青春期前后压力女性的 HPA 轴反应迟钝（目标 2）以及随后在怀孕期间经历的“第二次打击”压力源的长期后果（目标 3）来解决这一假设。

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).