Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa

描述（由申请人提供）：项目摘要/摘要本项目采用一种新颖的多学科方法来了解神经性厌食症（AN）的食欲和饮食行为的内分泌因素和神经回路。AN的特征是自我诱发的饥饿，与医学并发症、抑郁症和任何精神疾病的最高死亡率相关。治疗策略无效。在AN中，与进食行为有关的激素是异常的，现在可以使用功能性MRI（fMRI）用动态范例检查这些通路中的大脑区域。AN还与睾酮（T）缺乏有关，初步数据表明，生理替代导致体重指数（BMI）增加。对动物和人类的研究表明，T参与了进食行为。此外，试点数据表明，在涉及T缺乏的大脑区域的功能磁共振成像低激活，以响应食物相关的范例，这表明T可能会影响饮食行为，通过直接影响大脑，并在AN的治疗潜力。本申请的目的是研究以下假设：AN表型的特征在于参与食物动机和奖励的激素和神经回路的异常，并且T给药通过调节这些途径来改善结果。将对60名患有AN的女性和20名年龄在20-30岁的对照进行研究。在单次访视期间，受试者将接受BMI测量;空腹抽血测定激素水平（例如，生长激素释放肽、PYY）;评估食欲、情绪和饮食失调精神病理学;以及视觉食物和非食物刺激的fMRI。在食用标准化的混合餐后，将重新评估食欲和情绪，将获得一系列血液样本用于激素水平，并重复进行fMRI。在参与横断面访视的60例AN中，40例相对T缺乏的AN将以双盲设计随机接受低剂量透皮T（300 mcg qd），并将在4周和6个月时返回重复上述程序。Lawson博士是哈佛医学院（HMS）的医学讲师和马萨诸塞州总医院（MGH）的医学助理。她是在MGH神经内分泌单位的工作人员，并致力于她的大部分时间用于临床研究。她在研究AN激素异常方面的专业知识和建立的研究食欲神经回路的合作使她能够领导拟议的项目。今年6月，她通过HMS和马萨诸塞州理工学院（MIT）完成了医学硕士学位，并计划将她的培训范围扩大到包括高级统计学、神经解剖学和神经成像技术。她得到了MGH的大力支持，并可以充分利用神经内分泌部门，临床研究中心和哈佛催化剂资源。她的共同导师安妮·克里班斯基博士和吉尔·戈尔茨坦博士资金充足，并对劳森博士的研究方向进行了投资。该项目将支持Lawson博士在临床研究方面的培训，最终目标是成为一名独立的研究者，拥有将神经内分泌学和神经影像学技术相结合的专业知识，以更好地了解疾病的病理生理学。

DESCRIPTION (provided by applicant): Project Summary/Abstract This project takes a novel, multidisciplinary approach to understanding endocrine factors and neurocircuitry underlying appetite and eating behavior in anorexia nervosa (AN). AN, characterized by self-induced starvation, is associated with medical complications, depression, and the highest mortality of any psychiatric disease. Treatment strategies have been ineffective. Hormones involved in eating behavior are abnormal in AN, and brain regions in these pathways can now be examined with dynamic paradigms using functional MRI (fMRI). AN is also associated with testosterone (T) deficiency, and preliminary data indicates that physiologic replacement leads to an increase in body mass index (BMI). Studies in animals and humans implicate T in feeding behavior. Moreover, pilot data demonstrate hypoactivation by fMRI in brain regions implicated in T deficiency in response to a food-related paradigm, suggesting that T may influence eating behavior through direct effects on the brain, and has therapeutic potential in AN. The goal of this application is to investigate the hypothesis that the AN phenotype is characterized by abnormalities in hormones and neurocircuitry involved in food motivation and reward, and that T administration improves outcomes by modulating these pathways. 60 women with AN and 20 controls aged 20-30 will be studied. During a single visit, subjects will undergo measurement of BMI; a fasting blood draw for hormone levels (eg, ghrelin, PYY); assessment of appetite, mood and disordered eating psychopathology; and fMRI with visual food and non-food stimuli. After consumption of a standardized mixed meal, appetite and mood will be reassessed, serial blood samples will be obtained for hormone levels, and fMRI will be repeated. Of the 60 AN who participate in the cross-sectional visit, 40 AN with relative T deficiency will be randomized in a double-blind design to receive low-dose transdermal T (300mcg qd), and will return to repeat the above procedures at 4 weeks and 6 months. Dr. Lawson is an Instructor in Medicine at Harvard Medical School (HMS) and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. Her expertise in studying hormonal abnormalities in AN and established collaboration investigating the neurocircuitry of appetite positions her to lead the proposed project. She completed her Masters of Medical Science through HMS and Massachusetts Institute of Technology (MIT) in June, and plans to expand her training to include advanced statistics, neuroanatomy and neuroimaging technology. She is well-supported by MGH and has full access to Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst resources. Her co-mentors, Drs. Anne Klibanski and Jill Goldstein, are well-funded and invested in the direction of Dr. Lawson's research. This project will support Dr. Lawson's training in clinical research, with the ultimate goal of becoming an independent investigator with an expertise in combining neuroendocrinology and neuroimaging technology to better understand pathophysiology of disease.