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

基本信息

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
项目类别：
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

项目摘要

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).

项目概要/摘要限制性饮食失调 (R-ED) 是最致命的精神疾病之一，常见于拟议的 K23 重新提交将增加我们对 R-ED 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调节剂，我的流行病学研究表明，最终改善了 R-ED 的临床结果。 R-ED 中普遍存在广泛的免疫失调。雌激素缺乏在 R-ED 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。目前尚不清楚 R-中是否存在中枢神经系统 (CNS) 炎症（例如神经炎症） ED，以及针对新的 CNS 靶标的治疗是否对 R-ED 炎症有有益作用 K23-以患者为导向的研究职业发展奖申请采用创新的转化神经科学方法来检查雌激素缺乏和替代对炎症、脑通过利用正在进行的 R01 临床实用性调查，了解屏障功能和 R-ED 的核心症状。对患有 R-ED 的低雌激素女性进行 12 周雌激素替代治疗后，我们将评估其影响雌激素替代（与安慰剂）对炎症标志物（目标 1）、脑屏障的影响 – 使用用于表征体积、灌注和脑实质细胞外水的非侵入性神经成像（Aim 2）和核心饮食失调症状（目标 3）。劳伦·布莱索普 (Lauren Breithaupt) 成为一名独立的转化科学家，并开展了一项研究审查计划饮食失调中的神经炎症以确定新的治疗目标。对应于一个具体的培训目标，该目标将映射到 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，以及 (3) 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 阿诺德、大卫·阿尔索普、贝丝·史蒂文斯（科学顾问）和迭戈·皮扎加利（合作者）。