Blood Brain Barrier and Migraine: Effect on Therapy (Diversity Supplement)

血脑屏障和偏头痛：对治疗的影响（多样性补充）

• 批准号: 10404773
• 负责人: Tally Marie Milnes
• 金额: $ 3.23万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-29 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404773
• 关键词: Address; Affect; American; Analytical Chemistry; Animals; Behavioral; Bioinformatics; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cell Culture Techniques; Chronic disabling pain; Clinical; Communities; Data; Disease; Drug Delivery Systems; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Estrogen Receptor beta; Female; Future; Genetic; Goals; Gonadal Steroid Hormones; Headache; Headache Disorders; High Pressure Liquid Chromatography; Homeostasis; Hormones; In Situ; In Vitro; Inflammatory; Investigation; Knowledge; Learning; Light; Measures; Mediating; Methods; Migraine; Modality; Molecular; Movement; NHE1; Nervous system structure; Neuropeptides; Nociception; Outcome Measure; Pain; Pain intensity; Paper; Pathology; Pathway Analysis; Patients; Pattern; Perfusion; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Population; Prevalence; Prevention; Process; Production; Publishing; Recurrence; Regulation; Reporting; Research; Research Personnel; Risk; Role; Schools; Sensory; Sex Differences; Stroke; Sumatriptan; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Studies; Time; Training; Treatment Efficacy; Trigeminal System; Western Blotting; Woman; Work; Writing; Xenobiotics; animal tissue; bioinformatics network; blood-brain barrier disruption; brain endothelial cell; brain parenchyma; career; central sensitization; chronic pain; cutaneous allodynia; disability; experience; experimental study; female sex hormone; functional loss; graduate student; hormone regulation; immunocytochemistry; in vivo; in vivo evaluation; interest; laboratory experience; male; men; monolayer; nervous system disorder; neurovascular; pain outcome; pain perception; parent grant; prophylactic; relating to nervous system; sensory input; sensory stimulus; sex; sound; transgender; uptake

Project Summary Migraine is a primary headache disorder that affects women at a 3:1 ratio as compared to men which features a cyclical pattern of chronic pain attacks resulting from central sensitization of the trigeminal nervous system and various other neurovascular mechanisms to create a disease state wherein pain perception is intensely heightened. Migraine headaches are often triggered by environmental sensory stimuli, such as light and sound, wherein banal amounts of sensory input become noxious and induce headache suggesting that maladaptive association between the nociceptive and sensory processing networks could be the underlying cause. Neural damage leading to altered functional connectivity, increased production of inflammatory neuropeptides; and dysfunctional integration and processing of modality-specific sensory information are thought to be some mechanisms of migraine. Each of these is also implicated disruption of blood brain barrier homeostasis. Decreased integrity of the BBB can either increase or decrease the amount of xenobiotics entering the brain during disease providing a rational to study how therapeutic efficacy varies between the sexes during migraine. This proposal will determine if antimigraine blood to brain uptake differs between male and females because of physiological differences in the blood brain barrier by testing the hypothesis that sex hormone regulation of NHE1 through ERbeta in brain endothelial cells regulates sumatriptan blood-to-brain uptake in a sex dependent manner.

项目摘要 偏头痛是一种原发性头痛疾病，与男性相比，女性的比例为3：1，其特征是 三叉神经系统中枢致敏导致的慢性疼痛发作的周期性模式， 各种其他神经血管机制，以产生其中疼痛感知强烈增强的疾病状态。 偏头痛通常由环境感官刺激引发，例如光和声音，其中平庸的 大量的感觉输入变得有害并引起头痛，这表明适应不良的联想 可能是潜在的原因神经损伤导致 改变功能连接，增加炎症神经肽的产生;和功能障碍 特定感觉信息的整合和加工被认为是 偏头痛这些中的每一个也涉及血脑屏障稳态的破坏。完整性降低 血脑屏障可以增加或减少在疾病提供期间进入脑的外源性物质的量， 研究偏头痛的治疗效果在性别之间的差异是合理的。这项建议会 确定抗偏头痛药物的血脑摄取是否因生理因素而在男性和女性之间存在差异。 血脑屏障的差异，通过测试性激素调节NHE 1的假设， 脑内皮细胞中的ER β以性别依赖性方式调节舒马曲坦的血脑摄取。

项目成果

DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache.

• DOI: 10.3389/fphar.2020.615028
• 发表时间: 2020
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Levine A;Liktor-Busa E;Karlage KL;Giancotti L;Salvemini D;Vanderah TW;Largent-Milnes TM
• 通讯作者: Largent-Milnes TM

Inhibition of HSP90 Preserves Blood-Brain Barrier Integrity after Cortical Spreading Depression.

• DOI: 10.3390/pharmaceutics14081665
• 发表时间: 2022-08-10
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Palomino, Seph M.;Levine, Aidan A.;Wahl, Jared;Liktor-Busa, Erika;Streicher, John M.;Largent-Milnes, Tally M.
• 通讯作者: Largent-Milnes, Tally M.

Molecular mechanisms of hormones implicated in migraine and the translational implication for transgender patients.

• DOI: 10.3389/fpain.2023.1117842
• 发表时间: 2023
• 期刊: Frontiers in pain research (Lausanne, Switzerland)

Extracellular Alterations in pH and K+ Modify the Murine Brain Endothelial Cell Total and Phospho-Proteome.

• DOI: 10.3390/pharmaceutics14071469
• 发表时间: 2022-07-15
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Wahl, Jared R.;Vivek, Anjali;Palomino, Seph M.;Almuslim, Moyad;Cottier, Karissa E.;Langlais, Paul R.;Streicher, John M.;Vanderah, Todd W.;Liktor-Busa, Erika;Largent-Milnes, Tally M.
• 通讯作者: Largent-Milnes, Tally M.

Sex hormones regulate NHE1 functional expression and brain endothelial proteome to control paracellular integrity of the blood endothelial barrier.

• DOI: 10.1016/j.brainres.2021.147448
• 发表时间: 2021-07-15
• 期刊: Brain research
• 影响因子: 2.9