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).

项目摘要/摘要 限制性进食障碍(R-EDs)是最致命的精神疾病之一，在 青春期。建议的K23重新提交将增加我们对R-EDS中脑屏障的了解 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性调节剂， 最终导致R-EDS临床结果的改善。我的流行病学研究表明 广泛的免疫失调普遍存在于R-ED中。雌激素缺乏在R-EDs中很常见(~60%)和 由于雌激素对脑屏障的神经保护作用，可能会导致R-ED的神经炎症。它 目前尚不清楚R-R患者是否存在中枢神经系统(CNS)炎症(如神经炎症)。 EDS，以及针对新的中枢神经系统靶点的治疗是否对R-EDS的炎症有有利影响 K23-面向患者的研究职业发展奖申请使用创新的翻译 神经科学方法研究雌激素缺乏和替代对炎症、脑- 屏障功能和R-EDs的核心症状。通过利用正在进行的R01调查临床实用程序 我们将评估雌激素替代治疗对患有R-EDS的低雌激素女性患者12周的影响。 雌激素替代(与安慰剂相比)对炎性标志物(目标1)的影响，脑屏障-使用 无创神经成像表征脑实质的体积、灌注量和细胞外水(目的 2)和核心进食障碍症状(目标3)。与该项目对应的培训目标将支持Dr。 Lauren Breithaupt成为一名拥有研究审查计划的独立翻译科学家 进食障碍中的神经炎症以确定新的治疗靶点。这项研究的每个目标 与特定的培训目标相对应，这将映射到布雷索普特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，以及(3) 精神神经免疫学。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(联合导师)，Cynthia Bulik，Marco Loggia，Steven Arnold、David Alsop、Beth Stevens(科学顾问)和Diego Pizzagalli(合作者)。