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：这是一份为期五年的职业发展建议，旨在研究性别差异