Modeling anorexia nervosa with human pluripotent stem cells

描述（由申请人提供）：本项目的总体目标是确定神经性厌食症（AN）中疾病神经元的定义特征，在解决风险赋予遗传变异、多巴胺受体过量、无法感知奖励和AN的极端食物限制表型之间的相互作用的过程中。神经性厌食症是一种高度遗传的疾病，在精神疾病中死亡率最高，但缺乏有效的治疗方法。死亡时的高度营养不良状态阻碍了对脑组织的机械线索的研究。将体细胞遗传重编程为多能状态产生诱导多能干细胞（iPSC），并且已经使用人类细胞完成。所得iPSC与供体个体是同基因的，即，它们具有相似的遗传背景，并且可以分化成功能性神经元。因此，iPSC对于理解复杂的神经精神疾病（如AN）非常有吸引力，其中访问和分析神经组织是一个巨大的限速步骤。使用人类iPSC作为生物学工具来了解无法治疗的大脑疾病（如AN）的特殊价值不仅来自对大脑病理生理学的见解，而且还可能加速发现可以改变这种顽固性疾病进展的治疗方法。毫不奇怪，iPSCs的巨大潜力引发了研究人员对研究各种神经精神疾病个体的浓厚兴趣和兴奋，因为它们有可能揭示干预途径。这项合作提案中的AN研究提供了一个理想的环境，因为我们将通过国际AN治疗研究利用当地收集的AN青少年及其家庭队列，我们的小组正在评估临床过程，治疗结果，基因测序（Price Foundation赠款）和奖励途径的神经成像。因此，这一建议最大限度地发挥了创新技术组合的潜在科学影响，同时显著提高了其可行性。此外，AN的极端临床表型与风险赋予基因和感知奖励缺陷的新兴数据相结合，为拟议的研究提供了令人信服的理由。为此，具体目的是：（1）从患有AN的个体以及健康对照中衍生iPSC;（2）分析衍生自对照和AN iPSC的神经细胞的基因表达谱;以及（3）测试跨水平假设，例如，通过神经影像学观察导致多巴胺受体过量的神经机制，并确定遗传机制对这一过程的风险贡献。基于我们的假设，多能干细胞将被驱动分化为多巴胺能神经元，为将来的机制探索奠定基础。阐明基因、奖励机制和极端饮食行为之间的联系，不仅有可能产生神经性厌食症的机制和治疗知识，而且有可能产生新出现的肥胖流行病的机制和治疗知识。

DESCRIPTION (provided by applicant): The overarching goal of this project is to identify the defining characteristics of disease neurons in Anorexia Nervosa (AN), in the course of addressing the interplay between risk conferring genetic variations, excess of dopamine receptors, inability to sense reward and the extreme food restricting phenotype of AN. Anorexia nervosa is a highly heritable disorder with the highest mortality among psychiatric illnesses, yet lacking effective treatments. Highly malnourished status at death has obstructed the study of brain tissue for mechanistic clues. Genetic reprogramming of somatic cells to a pluripotent state produces induced pluripotent stem cells (iPSCs), and has been accomplished using human cells. The resulting iPSCs are isogenic to the donor individual, i.e., they carry a similar genetic background, and can be differentiated into functional neurons. Thus, iPSCs are extremely attractive for understanding complex neuropsychiatric diseases such as AN, where accessing and analyzing neural tissue is a tremendous rate-limiting step. The special value of using human iPSCs as a biological tool to understand untreatable brain disorders such as AN, comes not only from the promise of insights into brain pathophysiology, but also for the potential to accelerate the discovery of therapeutics that can modify progression of this adolescent-onset illness. Not surprisingly, the remarkable potential of iPSCs has sparked profuse interest and excitement in researchers studying individuals with a variety of neuropsychiatric disorders, because of their potential to reveal avenues for intervention. The study of AN in this collaborative proposal provides an ideal setting as we will leverage a locally collected cohort of adolescents with AN and their families via the International AN Treatment Study, who are being assessed by our group for clinical course, treatment outcome, genetic sequencing (Price Foundation grant) and neuroimaging of the reward pathway. Thus, this proposal maximizes the potential scientific impact of a combination of innovative technologies while remarkably enhancing their feasibility. Furthermore, the extreme clinical phenotype of AN combined with emerging data on risk conferring genes and deficits in sensing reward make a compelling case for the proposed study. To this end, the Specific Aims are: (1) to derive iPSCs from individuals with AN as well as healthy controls; (2) to analyze the gene expression profile of neural cells derived from controls and AN iPSCs; and (3) to test cross-level hypotheses, e.g., the neural mechanisms that result in the excess of dopamine receptors seen via neuroimaging and to determine the contribution of risk conferring genetic mechanisms to this process. The pluripotent stem cells will be driven to differentiate into dopaminergic neurons for future mechanistic explorations based on our hypotheses. Elucidating the links between genes, reward mechanisms and extremes of eating behaviors have the unmistakable potential of yielding mechanistic and therapeutic knowledge of not only anorexia nervosa but also of the emerging epidemic of obesity.