Deciphering the interactions of stress, corticosteroids, and Kiss1 neurons in reproduction and vasomotor symptoms in aging females

破译压力、皮质类固醇和 Kiss1 神经元在老年女性生殖和血管舒缩症状中的相互作用

• 批准号: 10424525
• 负责人: Ursula B. Kaiser
• 金额: $ 37.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424525
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Adverse effects; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Dementia; Development; Disease susceptibility; Distress; Dynorphin A; Dynorphins; Estradiol; Estrogens; Female; Fibrinogen; GABA Receptor; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Health; High temperature of physical object; Hormone secretion; Hormones; Hot flushes; Hypothalamic structure; Impairment; KISS1 gene; Knowledge; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Menopause; Modeling; Mus; Neurokinin B; Neurons; Neuropeptides; Obesity; Outcome; Pathway interactions; Patients; Peripheral; Physiologic Thermoregulation; Physiological; Play; Predisposition; Quality of life; Regulation; Reproduction; Reproductive Health; Risk; Role; Series; Severities; Sleep; Sleep disturbances; Stress; Structure of nucleus infundibularis hypothalami; Sweating; Symptoms; Tachykinin; Testing; Time; Vasodilation; Vasomotor; Woman; Work; adverse outcome; base; behavioral pharmacology; cardiometabolic risk; cardiovascular disorder risk; dementia risk; disorder risk; experience; gamma-Aminobutyric Acid; hypercortisolemia; hypothalamic pituitary gonadal axis; improved; insight; mouse genetics; mouse model; neural circuit; neuronal circuitry; neuroregulation; novel strategies; reproductive axis; reproductive function; reproductive senescence; restraint stress; sleep pattern; sleep quality; stress symptom; stressor; tool

PROJECT SUMMARY Vasomotor symptoms (VMS), also known as hot flashes, are common perturbations of perceived high temperature that women experience during menopause as a consequence of the depletion of estradiol levels. These VMS entail profuse sweating and peripheral vasodilation that can adversely affect quality of life in menopausal women, relevant to subsequent risk of cardiovascular disease and dementia. Recently, neurons producing the neuropeptides kisspeptin (encoded by the Kiss1 gene), neurokinin B (NKB, encoded by Tac2), and dynorphin (Dyn, encoded by Pdyn) and referred to as KNDy neurons in the hypothalamic arcuate nucleus of mice have been identified as mediators of hot flashes through a common pathway that also controls pulsatile GnRH secretion and the activity of the hypothalamic-pituitary-gonadal (HPG) axis. Based on this dual role of KNDy neurons, we hypothesize that factors that negatively impact reproductive function, such as stress and hypercortisolemia, act through KNDy neurons and will also affect thermoregulation (i.e., VMS) and sleep in menopausal patients. To this end, using mouse models of menopause and VMS, we aim to: 1) determine if these effects occur through direct regulation of Kiss1 or indirectly through regulation of Tac2 or Pdyn; and 2) determine if these effects occur on the KNDy neurons themselves and/or via neurons upstream of KNDy neurons—specifically, via GABAergic neurons. In addition, given the association of the menopausal decline of sex steroids with not only VMS but also disruption of sleep patterns, we aim to explore the relationships of stress, corticosteroids and KNDy neurons in the absence of sex steroids with sleep disruption. The successful completion of this proposal will offer important new mechanistic insights into the roles and effects of stress on KNDy neurons, the HPG axis, VMS, and associated sleep disturbances with the assistance of the Sleep Core. These insights will be critical to inform the development of new, safer and more effective tools to mitigate the effects of stress and of hot flashes in women, as studied in Project 1 and Project 2 of this SCORE application, and thereby improve reproductive health aging outcomes in women.

项目摘要 血管痉挛症状（VMS），也称为潮热，是一种常见的感觉高的扰动， 女性在绝经期间由于雌二醇水平耗尽而经历的温度。 这些VMS需要大量出汗和外周血管舒张，这可能对患者的生活质量产生不利影响。 绝经期妇女，与随后的心血管疾病和痴呆症的风险有关。最近，神经元 产生神经肽kisspeptin（由Kiss 1基因编码），神经激肽B（NKB，由Tac 2编码）， 和强啡肽（Dyn，由Pdyn编码），并被称为下丘脑弓状核中的KNDy神经元 的小鼠已被确定为通过一个共同的途径，也控制脉动性潮热的介质 GnRH分泌和下丘脑-垂体-性腺（HPG）轴的活动。基于这种双重角色， KNDy神经元，我们假设对生殖功能产生负面影响的因素，如压力和 高皮质醇血症，通过KNDy神经元起作用并且还将影响体温调节（即，VMS）和睡眠 更年期患者为此，使用绝经和VMS的小鼠模型，我们的目标是：1）确定是否 这些作用通过Kiss 1的直接调节或通过Tac 2或Pdyn的调节间接发生;和2） 确定这些作用是否发生在KNDy神经元本身和/或通过KNDy上游的神经元 神经元，特别是通过GABA能神经元。此外，考虑到绝经期妇女的 性类固醇不仅与VMS，但也扰乱睡眠模式，我们的目的是探讨的关系， 应激、皮质类固醇和KNDy神经元在不存在性类固醇的情况下与睡眠中断。成功 完成这一建议将提供重要的新机制的见解的作用和影响的压力， KNDy神经元、HPG轴、VMS以及在睡眠核心的协助下的相关睡眠障碍。 这些见解对于开发新的、更安全和更有效的工具以减轻 如在该SCORE应用的项目1和项目2中所研究的， 从而改善女性的生殖健康老龄化结果。