Estrogen's Neuroprotective Effects on the Brain-Barrier in Restrictive Eating Disorders

雌激素对限制性饮食障碍脑屏障的神经保护作用

• 批准号: 10525278
• 负责人: Lauren Breithaupt
• 金额: $ 18.95万
• 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: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525278
• 关键词: Adolescence; Adolescent; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Autoimmune Diseases; Autopsy; Blood; Brain; Brain imaging; Clinical; Competence; Data; Development; Development Plans; Eating Disorders; Estrogen Replacements; Estrogens; Female; Funding; Goals; Gonadal Steroid Hormones; Grant; Hormones; Image; Immune; Immune System Diseases; Immunology; Individual; Infection; Inflammation; Inflammatory; K-Series Research Career Programs; Knowledge; Link; Magnetic Resonance Imaging; Maps; Measurable; Measures; Mediating; Mental disorders; Mentors; Mentorship; Multimodal Imaging; National Institute of Mental Health; Neuraxis; Neurosciences; Outcome; Pathology; Perfusion; Peripheral; Permeability; Physiological; Placebos; Plasma; Population; Production; Proteins; Proteomics; Psychoneuroimmunology; Randomized Controlled Trials; Reaction; Relapse; Research; Risk; Sampling; Shapes; Structure of choroid plexus; Symptoms; Testing; Training; Water; Weight; Work; brain parenchyma; career; career development; epidemiology study; extracellular; healthy weight; immune function; improved; in vivo; inflammatory marker; innovation; neuroimaging; neuroinflammation; new therapeutic target; non-invasive imaging; novel; novel therapeutics; patient oriented research; perfusion imaging; programs; protein expression; restrictive eating; therapeutic target; translational neuroscience; translational scientist

PROJECT SUMMARY/ABSTRACT Restrictive eating disorders (R-EDs) are among the most lethal psychiatric illnesses and common in adolescence. The proposed K23 resubmission will increase our understanding of the brain barrier in R-EDs and test a novel therapeutic target (estrogen) as a neuroprotective moderator of brain barrier functioning, ultimately leading to improved clinical outcomes in R-EDs. My epidemiological research demonstrates that widespread immune dysregulation is prevalent in R-EDs. Estrogen deficiency is common in R-EDs (~60%) and may drive neuroinflammation in R-EDs due to the neuroprotective effects of estrogen on the brain barrier. It remains unclear whether central nervous system (CNS) inflammation (e.g., neuroinflammation) is present in R- EDs, and whether therapy directed at a novel CNS target has beneficial effects on inflammation in R-EDs This K23-Patient Oriented Research Career Development award application uses an innovate translational neuroscience approach to examine the impact of estrogen deficiency and replacement on inflammation, brain- barrier functioning, and core symptoms of R-EDs. By leveraging an ongoing R01 investigating the clinical utility of 12-weeks of estrogen replacement in hypoestrogenemic females with R-EDs, we will evaluate the influence of estrogen replacement (vs. placebo) on inflammation markers (Aim 1), the brain barrier – measured using non-invasive neuroimaging to characterize volume, perfusion, and brain parenchyma extracellular water (Aim 2), and core eating disorder symptoms (Aim 3). The training aim corresponding to this project will support Dr. Lauren Breithaupt in becoming an independent translational scientist with a program of research examining neuroinflammation in eating disorders to identify novel therapeutic treatment targets. Each aim of the study corresponds to a specific training goal, which will map onto three main areas of competency for Dr. Breithaupt : (1) advanced clinical neuroscience principles, (2) non-invasive imaging of brain barrier functioning, and (3) psychoneuroimmunology. Training goals will be implemented under the guidance of Drs. Kamryn Eddy (primary mentor), Marek Kubicki and Madhusmita Misra (co-mentors), Cynthia Bulik, Marco Loggia, Steven Arnold, David Alsop, Beth Stevens, (scientific advisors), and Diego Pizzagalli (collaborator).

项目总结/摘要 限制性进食障碍（R-EDs）是最致命的精神疾病之一， 青春期拟议的K23重新提交将增加我们对R-ED脑屏障的理解 并测试一种新的治疗靶点（雌激素）作为脑屏障功能的神经保护调节剂， 最终改善R-ED的临床结果。我的流行病学研究表明， 广泛的免疫失调在R-ED中普遍存在。雌激素缺乏在R-ED中很常见（约60%）， 由于雌激素对脑屏障的神经保护作用，可能导致R-ED中的神经炎症。它 仍然不清楚中枢神经系统（CNS）炎症（例如，神经炎症）存在于R- ED，以及针对新CNS靶点的治疗是否对R-ED中的炎症具有有益作用。 K23-以患者为导向的研究职业发展奖应用程序使用创新的翻译 神经科学的方法来检查雌激素缺乏和替代对炎症，脑， 屏障功能和R-ED的核心症状。通过利用正在进行的R 01研究临床效用 12周的雌激素替代治疗对低雌激素血症女性R-ED的影响，我们将评估 雌激素替代（与安慰剂）对炎症标志物（目的1），脑屏障-测量使用 非侵入性神经成像，以表征体积，灌注和脑实质细胞外水（目的 2）和核心进食障碍症状（目标3）。与此项目相对应的培训目标将支持博士。 Lauren Breithaupt成为一名独立的翻译科学家，他的研究项目包括： 神经炎症的饮食失调，以确定新的治疗治疗目标。研究的每一个目标 对应于具体的培训目标，这将映射到Breithaupt博士的三个主要能力领域： (1)先进的临床神经科学原理，（2）脑屏障功能的非侵入性成像，和（3） 心理神经免疫学培训目标将在Kamryn Eddy博士的指导下实施 （主要导师），Marek Kubicki和Madhusmita Misra（共同导师），Cynthia Bulik，Marco Loggia，Steven Arnold、大卫·艾尔索普、贝丝·史蒂文斯（科学顾问）和迭戈·皮扎加利（合作者）。