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: 10452257
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452257
• 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 (Brain); 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; Play; Prefrontal Cortex; Proteins; Proteomics; Research; Rewards; Risk; Rodent; Role; Sampling; Satiation; Serology; Signaling Protein; Starvation; Time; Variant; Weight; Weight Gain; Weight maintenance regimen; Woman; Work; base; biomarker-driven; cingulate cortex; cohort; cue reactivity; cytokine; diagnostic accuracy; follow-up; healthy weight; improved; inflammatory marker; insight; longitudinal analysis; longitudinal course; neural circuit; neuroinflammation; novel; pre-clinical; preclinical study; protein expression; reduced food intake; relating to nervous system; 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.

项目概要 这项小额赠款提案的目标是调查青少年炎症标志物的纵向变化 和患有低体重饮食失调 (LW-ED) 的年轻人与 (1) 体重变化和 (2) 奖励相关 神经回路激活。低体重饮食失调（LW-ED）；包括神经性厌食症及相关疾病 非典型变异是最致残和致命的精神疾病之一，在青春期很常见 (~15%)，并且经常演变成一种慢性疾病。新兴的临床前工作支持参与 对饥饿和体重变化做出反应的炎症标记物，表明炎症特征 可能代表划分疾病急性期的州特定生物标志物。我们之前的流行病学 与健康体重对照（HC）相比，这项工作提供了 LW-ED 免疫失调的证据。更多的 最近，使用一种新颖的蛋白质组血浆分析方法，我们的横截面试验数据表明 20 种蛋白质炎症标志物的水平区分 LW-ED 和 HC，表明炎症 LW-ED 可能取决于状态。来自临床前研究的额外数据提供了证据表明炎症 标记集中作用于与食欲和奖赏有关的区域，例如伏隔核（NAcc）和 海马体，表明异常炎症蛋白可能影响食物摄入和 驱动 LW-ED 的重量变化。然而，对炎症纵向过程的理解存在差距 LW-ED 中的蛋白质组学特征以及炎症特征和食物奖励回路之间的关系 在 LW-ED 中发挥作用。我们的中心假设是 LW-ED 中的异常炎症 (1) 代表一种状态 由体重减轻驱动的生物标志物，(2) 与食物奖励网络（海马体、 DLPFC、NAcc、dACC）。在体重增加的 LW-ED 个体中，我们预测食物奖励的中断 神经回路和炎症蛋白谱将稳定（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)，其中 BL 已对炎症蛋白谱进行了表征，此二次数据分析将检查 101 名女性青少年/年轻人（11.1-22.5 岁）的概况，其中 LW-ED（n=61）和 HC（n=40）年龄为 9- 一个月的随访（9M），使用一种新颖的蛋白质组学血浆分析方法来表征存储的图谱 血清学样本。这将允许 (1) 对 9M 处的剖面进行调查，以及 (2) 纵向分析（BL 至 9M）。将结合从 BL 到 9M 的体重变化、临床特征来研究概况 （包括饥饿和饱腹感评级）和功能磁共振成像食物线索反应数据。年龄匹配的健康对照将 用作阴性对照组以确定炎症特征的变化是否特定于 LW- ED组，而不是随时间随机波动。该提案将确定州特定的生物标志物和 低体重饮食失调（LW-ED）的治疗目标是众所周知的具有挑战性的疾病。