Sex differences in the role of gonadal hormones and the hypothalamus in migraine with aura.

性腺激素和下丘脑在先兆偏头痛中作用的性别差异。

• 批准号: 10523716
• 负责人: Andrea M Harriott
• 金额: $ 19.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523716
• 关键词: Abate; Acute; Address; Affect; Animal Model; Aptitude; Behavior; Behavioral; Brain region; Cells; Classic Migraine; Common Migraine; Craniotomy; Disease; Doctor of Philosophy; Estradiol; Estrogens; Estrus; Female; Foundations; Funding; Future; Gene Cluster; Gene Expression; General Hospitals; Genetic Transcription; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Headache; Headache Disorders; Hormonal; Hormones; Hypothalamic Hormones; Hypothalamic structure; Image; In Situ; Intervention; Knowledge; Lateral; Light; Machine Learning; Massachusetts; Measures; Menarche; Meningeal; Menopause; Menstruation; Mentors; Mentorship; Methods; Migraine; Modeling; Motor; Mus; Neurology; Neurons; Neuropeptides; Nociception; Nociceptors; Outcome Study; Pain; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Play; Population; Pre-Clinical Model; Progesterone; Recurrence; Research; Research Personnel; Rodent; Role; Sensory; Severities; Sex Differences; Speech; Spreading Cortical Depression; Stress; Sumatriptan; Supervision; Testing; Testosterone; Therapeutic Intervention; Training; Training Programs; Trigeminal Nuclei; Trigeminal Pain; Trigeminal System; Visual; Woman; allodynia; behavioral study; career; career development; cell type; clinical candidate; cost; cutaneous allodynia; differential expression; disability; epidemiology study; experience; experimental study; hypocretin; in vivo; instructor; male; mechanical allodynia; medical schools; men; minimally invasive; novel; optogenetics; pain behavior; painful neuropathy; pre-clinical; preclinical study; response; sex; sex disparity; sexual dimorphism; single-cell RNA sequencing; skills; social; spreading depression; targeted treatment; transcriptomics

Project Summary/Abstract: This is a five-year career development proposal examining sex differences in gonadal hormone and hypothalamic involvement in migraine with aura using cortical spreading depression as a model. The candidate is an Instructor at Harvard Medical School and a physician at the Massachusetts General Hospital in the Department Neurology, Division of Headache and Neuropathic Pain. This proposal advances the candidate’s prior experience with a combination of optogenetic, chemogenetic, machine learning and transcriptomic approaches to studying sex differences in migraine mechanisms in vivo. This proposal also interfaces with the candidate’s clinical expertise in treating migraine and other disabling headache disorders. The training plan focuses on enhancing the candidate’s aptitude in the field of sex differences migraine research and gaining discrete skills in cutting edge experimental methods through an intensive supervised training experience incorporating the expert knowledge of co-mentors Prof. Cenk Ayata, MD PhD who specializes in spreading depression and Prof. Ursula Kaiser, MD who specializes in hypothalamic, sex and gonadal hormones. The training program will enable the candidate’s transition to an independent research career whose long-term goal is to discover sex dependent mechanisms of migraine. Migraine accounts for considerable global suffering and disproportionately affects women. Cortical spreading depression (SD), a slow wave of neuronal and glial depolarization, is responsible for migraine with aura and is widely used as a preclinical migraine model. SD can activate meningeal nociceptors and sensitize second order neurons in the trigeminal nucleus caudalis (TNC). Furthermore, minimally invasive optogenetic SD produces periorbital allodynia and increases mouse grimace, behavioral evidence of trigeminal nociceptive activation. That migraine starts after menarche, worsens during menstruation, and abates after menopause implicates gonadal hormones in migraine. Moreover, a growing body of evidence supports a role for the hypothalamus, one of the most sexually dimorphic regions of the brain, in migraine. Activation of hypothalamic neurons, including those expressing neuropeptide orexin, could act to mitigate the impact of SD on trigeminal pain via descending inhibition of TNC neurons. However, sex differences in gonadal hormone modulation of migraine-relevant behavior or the role of the hypothalamus has not been systematically investigated. Specifically, this proposal aims to (1) investigate sex differences in female and male gonadal hormone modulation of SD-induced migraine- relevant behaviors, (2) examine sex and hormonal influences on SD-induced lateral hypothalamic gene expression and (3) examine sex differences in orexinergic modulation of SD-induced trigeminal pain behavior. At the end of the proposed experiments, study results are expected to enhance the fundamental understanding of mechanisms of sex differences in migraine with aura and contribute to uncovering putative targets for subsequent mechanistic studies of sex specific hypothalamic neuronal involvement in migraine.

项目摘要/摘要：这是一项为期五年的职业发展建议，研究了性别差异 性腺马酮和下丘脑与Aura在偏头痛中的参与使用皮质扩散抑郁作为一种 模型。该候选人是哈佛医学院的教练，也是马萨诸塞州一般的身体 头痛和神经性疼痛的部门神经病学医院。该提议推动了 候选人的先前经验，结合了光学遗传学，化学遗传学，机器学习和 研究体内偏头痛机制性别差异的转录组方法。这项建议也是如此 与候选人在治疗偏头痛和其他残疾标头疾病方面的临床专业知识的界面。 培训计划的重点是增强候选人在性别差异领域的能力偏头痛研究 并通过深入监督培训获得尖端实验方法的离散技能 经验增加了专门从事的专业Cenk Ayata教授的专业知识 扩散抑郁症和医学博士Ursula Kaiser教授，专门从事下丘脑，性和性腺激素。 培训计划将使候选人向独立研究职业过渡，其长期 目标是发现偏头痛的性依赖机制。 偏头痛考虑了全球苦难，并对妇女产生不成比例的影响。皮质扩散 抑郁（SD）是神经元和神经胶质沉积的慢波，负责偏头痛，Aura，IS 广泛用作临床前偏头痛模型。 SD可以激活脑膜伤害感受器和灵敏度二阶 三叉神经核（TNC）中的神经元。此外，微创光遗传学SD产生 周围异常性痛和增加小鼠鬼脸，三叉神经伤害性激活的行为证据。那 偏头痛在初潮之后开始，在月经期间恶化，并在更年期含义后减弱 偏头痛中的激素。此外，越来越多的证据支持下丘脑的作用，其中之一 大脑的大多数性二态性区域，偏头痛。下丘脑神经元的激活，包括 表达神经肽蛋白可以通过下降来减轻SD对三叉神经疼痛的影响 抑制TNC神经元。但是，与偏头痛相关的性腺激素调节的性别差异 行为或下丘脑的作用尚未系统地研究。具体来说，该提议 旨在（1）研究女性和男性性腺激素调节SD诱导偏头痛的性别差异 相关行为，（2）检查对SD诱导的下丘脑基因的性别和马的影响 表达和（3）检查SD诱导的三叉神经疼痛行为的甲状腺素能调节中的性别差异。 在拟议的实验结束时，预计研究结果将增强基本理解 偏头痛的性别差异机制与AURA，并有助于发现假定的目标 随后的性别特异性下丘脑神经元参与偏头痛的机理研究。