Molecular characterization of metabolic reprogramming in anorexia nervosa

神经性厌食症代谢重编程的分子特征

• 批准号: 10675708
• 负责人: Youngjung Kim
• 金额: $ 16.74万
• 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: 2022-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675708
• 关键词: Acute; Adult; Aftercare; Age; Anorexia Nervosa; Back; Binge Eating; Bioenergetics; Biological Assay; Blood; Body Weight decreased; Body mass index; Brain Diseases; Cell Energetics; Cell model; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Coupled; Data; Data Science; Doctor of Philosophy; Eating Behavior; Eating Disorders; Ethnic Origin; FDA approved; Fasting; Feeding behaviors; Foundations; Gender; Gene Expression; Gene Expression Profiling; General Population; Genetic study; Genomics; Glucose; Goals; Homeostasis; Human; Hunger; Hyperglycemia; Hypoglycemia; Individual; Intervention; Lead; Libraries; Life; Lipids; Medicine; Mental disorders; Mentors; Metabolic; Metabolic Diseases; Metabolism; Microglia; Modeling; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; National Institute of Mental Health; Nutrient; OGTT; Outcome; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Physicians; Plasma; Precision therapeutics; Premature Mortality; Principal Investigator; Psychiatrist; Psychiatry; Quality of life; Recording of previous events; Regulation; Relapse; Reporting; Research; Role; Science; Scientist; Starvation; Stimulus; Symptoms; Testing; Therapeutic; Thinness; Training; Translational Repression; Translational Research; Underweight; Up-Regulation; Weight; Weight Gain; Woman; blood glucose regulation; brain based; career development; drug candidate; experience; feeding; flexibility; glucose metabolism; glucose uptake; high dimensionality; increased appetite; lipid metabolism; metabolomics; molecular modeling; mortality; neural; novel; novel therapeutics; pharmacologic; programs; recruit; relapse patients; relapse prevention; response; restrictive eating; reward circuitry; screening; single-cell RNA sequencing; small molecule; stressor; therapeutically effective; transcriptome sequencing; translational pipeline; translational research program; weight maintenance

PROJECT SUMMARY . Anorexia nervosa (AN) is a psychiatric illness with the single highest premature mortality rate. Despite this, there are no robust treatment options for adult patients with AN. In addition, more than 70% of patients relapse within 25 years after treatment creating a chronic course with poor quality of life. The lack of effective therapeutics is coupled with the lack of molecular mechanisms of AN. Recent genomic studies have identified a “metabolic axis” in AN, but the exact role for metabolism is unclear. Data from acutely weight-restored women with AN (WR-AN) demonstrate significant differences in their oral glucose tolerance tests (OGTT), lipid profiles, and other metabolism markers compared to age- and weight- matched healthy control women (HC). Of note, OGTT in WR-AN is highly reactive in clearing the hyperglycemic peak to return to homeostasis, suggesting that such a bioenergetic efficiency in handling nutrient stressors may be the basis for relapse in AN. We hypothesized that such systemic differences in metabolism would start with the molecular building blocks to generate metabolic functional differences in cells of WR-AN vs. HC, which may be leveraged for novel therapeutics for relapse prevention. Building on our preliminary data, we will test our hypothesis with 3 research aims: (1) molecular characterization of WR-AN and HC using cellular functional assays and gene expression analysis, (2) characterization of WR-AN during the first year of weight maintenance known for its high relapse rates, and (3) ex vivo high-throughput drug and nutrient screening in cellular models of AN derived from WR-AN. The studies proposed herein will provide the groundwork towards a molecular model of AN and generate a translational pipeline for precision therapeutics aimed at enhancing science and medicine for an illness with dismal outcomes, no treatments, and no molecular mechanisms. The proposed research will be accompanied by 2 years of mentored training in K99, where the principal investigator (PI) Dr. Youngjung Kim, MD, PhD, will obtain systematic training in (T1) advanced data science, (T2) translational science, (T3) comprehensive mastery of clinical trials, (T4) career development, and (T5) responsible conduct or research. Proposed training plan builds directly on the PI’s physician-scientist training with experience in molecular experimentation in models of metabolic disorders, clinical research into the metabolism of AN, and clinical independence as an eating disorder psychiatrist. On this foundation, training will be guided by a star team of mentors, including: primary mentor Dr. Roy Perlis, MD, MSc; co-mentors Drs. Madhusmita Misra, MD, MPH and Kamryn Eddy, PhD; advisors Drs. Maurizio Fava, MD and Tom Hildebrandt, PsyD. With guidance from this exceptional mentoring team, the PI will successfully transition to research independence by R00 and succeed in building and leading her independent translational research program.

项目摘要。 神经性厌食症（AN）是一种过早死亡率最高的精神疾病。尽管如此，有 对于成年 AN 患者来说，没有强有力的治疗选择。此外，超过70%的患者会在短时间内复发。 治疗 25 年后形成慢性病程，生活质量较差。缺乏有效的治疗方法是 再加上缺乏 AN 的分子机制。 最近的基因组研究已经确定了 AN 中的“代谢轴”，但代谢的确切作用是 不清楚。来自患有 AN (WR-AN) 的体重急剧恢复女性的数据表明，她们的体重存在显着差异。 与年龄和体重相比，口服葡萄糖耐量试验 (OGTT)、血脂谱和其他代谢标志物 匹配的健康对照女性（HC）。值得注意的是，WR-AN 中的 OGTT 在清除高血糖方面具有高度反应性。 达到恢复稳态的峰值，这表明处理营养应激源的这种生物能效率可能 是 AN 复发的基础。我们假设新陈代谢的这种系统性差异始于 WR-AN 与 HC 细胞中产生代谢功能差异的分子构件，这可能 可用于预防复发的新疗法。根据我们的初步数据，我们将测试我们的 具有 3 个研究目标的假设：(1) 使用细胞功能对 WR-AN 和 HC 进行分子表征 测定和基因表达分析，(2) 体重维持第一年期间 WR-AN 的表征 以其高复发率而闻名，以及（3）细胞模型中的离体高通量药物和营养物筛选 AN 源自 WR-AN。本文提出的研究将为分子模型提供基础 AN 并生成旨在增强科学和医学的精准治疗的转化管道 对于一种结果令人沮丧、没有治疗方法、也没有分子机制的疾病。 拟议的研究将伴随着 K99 为期 2 年的指导培训，其中校长 研究员（PI）Youngjung Kim博士，MD，PhD，将获得（T1）高级数据科学的系统培训，（T2） 转化科学，(T3) 全面掌握临床试验，(T4) 职业发展，(T5) 负责任的行为或研究。拟议的培训计划直接建立在 PI 医师科学家培训的基础上 具有代谢紊乱模型分子实验、临床研究的经验 AN 的代谢，以及作为饮食失调精神病学家的临床独立性。在此基础上，培训将 由明星导师团队指导，包括： 首席导师 Roy Perlis 博士，医学博士、理学硕士；共同导师博士。 Madhusmita Misra，医学博士、公共卫生硕士和 Kamryn Eddy，博士；顾问博士。 Maurizio Fava 医学博士和 Tom Hildebrandt， 心理学博士。在这个杰出的指导团队的指导下，PI 将成功过渡到研究 R00 的独立性，并成功建立和领导她的独立转化研究项目。