Molecular characterization of metabolic reprogramming in anorexia nervosa

项目总结。 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，还有 对于患有AN的成年患者来说，没有强有力的治疗选择。此外，超过70%的患者在 治疗25年后形成慢性病程，生活质量差。缺乏有效的治疗方法是 加之缺乏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”，但新陈代谢的确切作用是 不清楚。来自体重急剧恢复的患有(WR-AN)的女性的数据显示，在她们的 口服葡萄糖耐量试验(OGTT)，血脂和其他代谢标记物与年龄和体重的比较- 与之匹配的健康对照组(HC)。值得注意的是，WR-AN中的OGTT在清除高血糖方面具有很高的反应性 高峰期回到动态平衡，表明这种生物能量效率在处理营养压力源时可能 是一种疾病复发的基础。我们假设，新陈代谢的这种系统性差异将始于 WR-AN与HC细胞产生代谢功能差异的分子构建块，这可能 被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 假设：(1)基于细胞功能的WR-AN和HC的分子表征 检测和基因表达分析，(2)WR-AN在维持体重第一年的特性 以其高复发率而闻名，以及(3)体外高通量药物和细胞模型中的营养筛选 从WR-An派生的。本文提出的研究将为分子模型的建立奠定基础。 并为旨在提高科学和医学水平的精确治疗提供一条翻译管道 对于一种结果令人沮丧的疾病，没有治疗方法，也没有分子机制。 拟议的研究将伴随着两年的K99指导培训，在那里校长 调查员(PI)金永贞博士，医学博士，博士，将接受(T1)高级数据科学的系统培训(T2) 翻译科学，(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的医生-科学家培训的基础上 在代谢紊乱模型的分子实验方面有经验，临床研究 安的新陈代谢，以及作为饮食障碍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：主要导师Roy Perlis博士，医学博士，理学硕士；共同导师Dr. MadHusmita Misra医学博士，公共卫生硕士和Kamryn Eddy博士，医学顾问Maurizio Fava博士和Tom Hildebrandt博士， 精神错乱。在这个杰出的指导团队的指导下，PI将成功过渡到研究 在R00之前独立，并成功地建立并领导了她的独立翻译研究项目。

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.