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

本建议书中概述的培训活动、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的近期职业目标，并获得成功实现成为独立主要研究者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压力易感性的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，专注于了解复杂系统中的神经生物学和行为，旨在更准确地代表与生命相关的生活体验。PI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，该战略由主要导师Tracy Bale博士和咨询委员会指导。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，这是一个世界知名的研究机构，拥有令人难以置信的最先进的研究设施。拟议的研究将在5年内进行，而培训部分将主要在第1年和第2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，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，可以检查青春期应激的后果以及这种经历如何与以后的激素变化（如怀孕）相互作用。在该模型中，青春期应激仅在妊娠期间引起下丘脑-垂体-肾上腺（HPA）轴对急性应激的反应中断。令人兴奋的初步数据暗示PVN的长期表观遗传变化与妊娠的独特神经内分泌环境相互作用，引起应激失调。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别孕烯醇酮增加的相互作用引起的，并且这种失调代表了增加疾病风险的潜在因素。三个具体目标将通过确定PVN GABA系统中青春期应激诱导的改变是由于稳定的染色质修饰（目标1），PVN内的别孕烯醇酮如何促进青春期应激女性中的钝化HPA轴反应（目标2），以及怀孕期间经历的后续“二次打击”应激源的长期后果（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).