Molecular characterization of metabolic reprogramming in anorexia nervosa

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，在 对于成人AN患者没有稳健的治疗选择。此外，超过70%的患者在 治疗后25年，形成慢性病程，生活质量差。缺乏有效的治疗方法， 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 不清楚急性体重恢复的AN女性（WR-AN）的数据显示， 口服葡萄糖耐量试验（OGTT）、血脂谱和其他代谢标志物与年龄和体重相比， 匹配的健康对照女性（HC）。值得注意的是，WR-AN中的OGTT在清除高血糖中具有高度反应性， 峰值恢复到稳态，这表明在处理营养压力时，这种生物能量效率可能 是AN复发的基础。我们假设这种代谢的系统性差异始于 分子构建模块在WR-AN与HC的细胞中产生代谢功能差异，这可能 用于预防复发的新疗法。基于我们的初步数据，我们将测试我们的 假设有3个研究目标：（1）WR-AN和HC的分子表征，使用细胞功能 测定和基因表达分析，（2）在体重维持的第一年期间WR-AN的表征 以其高复发率而闻名，和（3）在细胞模型中进行离体高通量药物和营养筛选 从WR-AN衍生的AN。本文提出的研究将为建立分子模型奠定基础 并为旨在加强科学和医学的精确治疗产生一个转化管道 没有治疗方法，也没有分子机制。 拟议的研究将伴随着2年的K99指导培训，其中校长 研究者（PI）Youngjung Kim博士，医学博士，博士，将获得（T1）高级数据科学，（T2） 转化科学，（T3）全面掌握临床试验，（T4）职业发展，和（T5） 负责任的行为或研究。拟定的培训计划直接建立在PI的医生-科学家培训基础上 具有代谢紊乱模型的分子实验经验， AN的代谢，以及作为进食障碍精神病医生的临床独立性。在此基础上， 由一个星星导师团队指导，包括：主要导师罗伊·佩里斯博士，医学博士，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Maurizio Fava博士和Tom Hildebrandt博士， 心理学博士有了这个特殊的指导团队的指导，PI将成功地过渡到研究 通过R 00独立，并成功地建立和领导她的独立翻译研究计划。

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.