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.

项目摘要 这项小额拨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）奖励有关的低体重饮食失调（LW-ED）的年轻人 神经回路激活低体重进食障碍（LW-ED）;包括神经性厌食症和相关 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。 （约15%），并经常演变成慢性疾病。新兴的临床前工作支持参与 炎症标志物对饥饿和体重变化的反应，表明炎症特征 可以代表划分疾病急性期的状态特异性生物标志物。我们先前的流行病学 研究提供了与健康体重对照组（HC）相比LW-ED免疫失调的证据。更 最近，使用一种新的蛋白质组血浆分析方法，我们的横断面试验数据表明， 20种蛋白质炎症标志物的水平区分LW-ED和HC，表明LW-ED中的炎症 LW-ED可能依赖于状态。来自临床前研究的额外数据提供了炎症性 标记物集中作用于涉及食欲和奖赏的区域，如丘脑核（NAcc）和 海马，表明异常炎症蛋白可能影响食物摄入的途径， LW-ED中的驱动器重量变化。然而，在理解炎症的纵向过程方面存在差距 LW-ED中的蛋白质组学特征以及炎症特征与食物奖赏回路之间的关系 在LW-ED中发挥作用。我们的中心假设是LW-ED的异常炎症（1）代表了一种状态 由体重减轻驱动的生物标志物，和（2）与食物奖赏网络（海马， DLPFC、NAcc、dACC）。在体重增加的LW-ED患者中，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R 01（MH 103402），其中 炎症蛋白质谱已经在BL表征，这种二次数据分析将检查 101例9岁以下LW-ED（n=61）和HC（n=40）女性青少年/年轻成人（11.1-22.5岁）的特征 使用一种新的蛋白质组学血浆谱分析方法对储存的血浆中的谱进行表征， 血清样本这将允许（1）调查9 M处的剖面，以及（2）纵向分析（BL至 9M）。将结合从BL至9 M的体重变化、临床特征 （包括饥饿和饱腹感评级）和fMRI食物线索反应性数据。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异于LW-1。 艾德组，而不是随时间随机波动。该提案将确定国家特定的生物标志物， 低体重进食障碍（LW-ED）是众所周知的具有挑战性的疾病。