Longitudinal Immune Dysregulation in Low-Weight Eating Disorders and Association with Weight Fluctuations

低体重饮食失调的纵向免疫失调及其与体重波动的关联

• 批准号: 10558634
• 负责人: Lauren Breithaupt
• 金额: $ 8.4万
• 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: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558634
• 关键词: Acute; Adolescence; Adolescent; Adolescent and Young Adult; Age; Anorexia Nervosa; Anterior; Anti-Inflammatory Agents; Applications Grants; Autoimmune Diseases; Biological Markers; Body Weight; Body Weight Changes; Body Weight decreased; Brain region; Characteristics; Chronic; Clinical; Clinical Data; Control Groups; Corpus striatum structure; Cues; Data; Data Analyses; Desire for food; Disease; Disease remission; Dopamine; Dorsal; Eating; Eating Disorders; Epidemiology; Exhibits; Female Adolescents; Food; Functional Magnetic Resonance Imaging; Goals; Grant; Hippocampus; Human; Hunger; Immune; Immune System Diseases; Immune signaling; Individual; Infection; Inflammation; Inflammatory; Intervention; Investigation; Lateral; Link; Longitudinal Studies; Mediating; Mental disorders; Monitor; Neurobiology; Nucleus Accumbens; Pathway interactions; Patients; Plasma; Plasma Proteins; Prefrontal Cortex; Proteins; Proteomics; Research; Rewards; Risk; Rodent; Sampling; Satiation; Serology; Signaling Protein; Starvation; Time; Variant; Weight; Weight Gain; Weight maintenance regimen; Woman; Work; biomarker driven; cingulate cortex; cohort; cue reactivity; cytokine; diagnostic accuracy; follow-up; healthy weight; improved; inflammatory marker; insight; longitudinal analysis; longitudinal course; neural; neural circuit; neuroinflammation; novel; pre-clinical; preclinical study; protein expression; reduced food intake; response; reward circuitry; specific biomarkers; therapeutic target; therapy development; trend; uptake; young adult

Project Summary The goal of this small grant proposal is to investigate longitudinal changes in inflammatory markers in adolescents and young adults with low-weight eating disorders (LW-EDs) in relation to (1) weight change and (2) reward neural circuitry activation. Low-weight eating disorders (LW-EDs); including anorexia nervosa and related atypical variants, are among the most disabling and fatal psychiatric illnesses, are common in adolescence (~15%), and often evolve into a chronic condition. Emerging preclinical work supports the involvement of inflammatory markers in response to starvation and changes in body weight, suggesting inflammatory profiles may represent a state-specific biomarker demarcating the acute stage of illness. The Our prior epidemiological work provides evidence of immune dysregulation in LW-EDs compared to healthy-weight controls (HC). More recently, using a novel proteomic plasma profiling approach, our cross-sectional pilot data demonstrate that levels of 20 protein inflammation markers distinguish between LW-EDs and HC, suggesting that inflammation in LW-EDs might be state-dependent. Additional data from pre-clinical studies provides evidence that inflammatory markers act centrally on regions involved in appetite and reward such as the nucleus accumbens (NAcc) and hippocampus, indicating pathways through which aberrant inflammatory proteins might impact food intake and drive weight change in LW-EDs. However, there is a gap in understanding the longitudinal course of inflammation proteomic profiles in, LW-EDs and relationships between inflammatory profiles and food reward circuitry functioning in LW-EDs. Our central hypothesis is that aberrant inflammation in LW-EDs (1) represents a state biomarker driven by weight loss, and (2) is associated with dysregulation in food reward networks (hippocampus, DLPFC, NAcc, dACC). Among individuals with LW-EDs who gain weight, we predict that disruption in food reward neural circuitry and inflammation protein profiles will stabilize (anti-inflammatory protein expression levels increase, and pro-inflammatory levels decrease). Leveraging a recently completed R01 (MH103402) in which inflammation protein profiles have already been characterized at BL, this secondary data analysis will examine profiles of 101 female adolescents/young adults (11.1-22.5 years) with LW-EDs (n=61) and HC (n=40) at 9- month follow-up (9M) using a novel proteomics plasma profiling approach to characterize profiles in stored serological samples. This will allow for (1) investigation of profiles at 9M, and (2) longitudinal analyses (BL to 9M). Profiles will be investigated in combination with weight change from BL to 9M, clinical characteristics (including hunger and satiety ratings), and fMRI food cues reactivity data. Age-matched healthy controls will be used as a negative control group to determine whether changes in inflammatory profiles are specific to the LW- ED group, rather than random fluctuations over time. This proposal will identify state-specific biomarkers and therapeutic targets in low-weight eating disorders (LW-EDs), which are notoriously challenging disorders to treat.

项目摘要 这项小赠款提案的目的是调查青少年炎症标志物的纵向变化 与（1）体重变化和（2）奖励有关的年轻人和低体重饮食失调（LW-ED） 神经电路激活。低体重饮食失调（LW-EDS）；包括神经性厌食症和相关性 非典型变体是最残疾和致命的精神病，在青春期很常见 （〜15％），通常演变为慢性病。新兴的临床前工作支持 炎症标记响应饥饿和体重的变化，表明炎症特征 可能代表特定于州特异性的生物标志物，以划定急性疾病的阶段。我们先前的流行病学 与健康重量对照（HC）相比，工作提供了LW-EDS免疫失调的证据。更多的 最近，使用一种新型的蛋白质组学血浆分析方法，我们的横截面试验数据表明， 20种蛋白质炎症标记的水平区分LW-EDS和HC，表明在 LW-ED可能是国家依赖的。临床前研究的其他数据提供了证据表明炎症 标记集中于胃口和奖励的区域，例如伏隔核（NACC）和 海马，指示异常炎性蛋白可能影响食物摄入和 驱动LW-ED的重量变化。但是，了解炎症的纵向过程存在差距 蛋白质组学曲线，LW-EDS以及炎症轮廓与食物奖励电路之间的关系 在LW-EDS中功能。我们的核心假设是LW-EDS（1）中异常炎症代表一个状态 由体重减轻驱动的生物标志物，（2）与食物奖励网络中的失调有关（海马，， DLPFC，NACC，DACC）。在体重增加的LW-EDS的个体中，我们预测食物奖励的破坏 神经回路和炎症蛋白轮廓将稳定（抗炎蛋白表达水平 增加，促炎水平降低）。利用最近完成的R01（MH103402） 炎症蛋白轮廓已经在BL上进行了表征，该二次数据分析将检查 在9-处的101名女性青少年/年轻人（11.1-22.5岁）的剖面 使用一种新型的蛋白质组学等离子体分析方法来表征存储的曲线 血清学样本。这将允许（1）在9M处研究剖面，（2）纵向分析（BL至 9m）。轮廓将与从BL到9M的重量变化相结合，临床特征的变化 （包括饥饿和饱腹感）以及fMRI食品提示反应性数据。年龄匹配的健康对照将是 用作负面对照组，以确定炎症特征的变化是否特定于LW- ED组，而不是随着时间的流逝而随机波动。该建议将确定特定州特定的生物标志物和 低体重饮食失调（LW-EDS）的治疗靶标，众所周知，这是对治疗的挑战。