Modeling anorexia nervosa with human pluripotent stem cells

用人类多能干细胞模拟神经性厌食症

• 批准号: 8243213
• 负责人: Vikas Duvvuri
• 金额: $ 23.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243213
• 关键词: AN5; Action Potentials; Address; Adolescent; Alleles; Anorexia Nervosa; Binding; Bioinformatics; Biological; Biological Assay; Biological Markers; Brain; Brain Diseases; Calcium-Activated Potassium Channel; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Cessation of life; Chemosensitization; Clinical; Code; Complex; Corpus striatum structure; Data; Diagnosis; Disease; Dopamine; Dopamine Receptor; Eating Behavior; Eating Disorders; Epidemic; Exons; FDA approved; Family; Fibroblasts; Food; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Glutamate Receptor; Goals; Grant; Human; Human Genetics; Hyperactive behavior; Image; Individual; International; Intervention; Knowledge; Laboratories; Lead; Length; Link; Malnutrition; Measures; Midbrain structure; Modeling; Molecular; Molecular Profiling; N-Methylaspartate; National Institute of Mental Health; Nerve; Neurodevelopmental Disorder; Neurons; Obesity; Onset of illness; Pacemakers; Pathway interactions; Phenotype; Pluripotent Stem Cells; Price; Process; Proteins; Psychopathology; RNA; Recruitment Activity; Research Personnel; Rewards; Risk; Sampling; Sensory Receptors; Signal Transduction; Single Nucleotide Polymorphism; Skin; Somatic Cell; Staging; Strategic Planning; System; Techniques; Testing; Therapeutic; Time; Tissues; Transcript; Treatment outcome; Variant; Woman; base; biosignature; brain tissue; cell type; clinical phenotype; cohort; cost; disease characteristic; dopaminergic neuron; effective therapy; end stage disease; genetic variant; genome-wide; induced pluripotent stem cell; innovation; innovative technologies; insight; interest; mortality; neural precursor cell; neurochemistry; neuroimaging; neuromechanism; neuropsychiatry; neurotransmission; receptor binding; receptor density; relating to nervous system; repository; tool

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. PUBLIC HEALTH RELEVANCE: Anorexia nervosa (AN) is a highly heritable disorder with the highest mortality among psychiatric illnesses, yet lacking effective treatments. Genetic reprogramming of somatic cells to a pluripotent state produces induced pluripotent stem cells (iPSC), and that are isogenic to the donor individual, i.e., they carry a similar genetic background. We will compare the gene expression profile of neural cells derived from controls and AN iPSC and test the contribution of risk-conferring genetic variants to the neuronal phenotype.

描述（由申请人提供）：该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的风险之间的相互作用，多巴胺受体的过量，无法进行奖励和极端的食物限制对An的现象。神经性厌食症是一种高度遗传的疾病，在精神病中死亡率最高，但缺乏有效的治疗方法。高度营养不良的死亡状态阻碍了对机械线索的脑组织的研究。体细胞对多能状态的遗传重编程会产生诱导的多能干细胞（IPSC），并已使用人类细胞完成。所得的IPSC对供体个体具有不同根性，即它们具有相似的遗传背景，并且可以分化为功能性神经元。因此，IPSC对于理解复杂的神经精神疾病（例如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制步骤。使用人IPSC作为一种生物学工具来理解不可治疗的脑疾病（例如AN）的特殊价值不仅源于对脑部病理生理学的见解的承诺，而且还源于可能加速可以改变这种青少年疾病进展的治疗剂的潜力。毫不奇怪，IPSC的巨大潜力引发了研究人员的研究人员，因为研究人员有各种神经精神疾病，因为它们有可能揭示干预途径的潜力。对本协作提案的研究提供了理想的环境，因为我们将通过国际AN治疗研究来利用与AN及其家人的当地收集的青少年群体，他们正在由我们的小组评估临床课程，治疗结果，基因测序（价格基础赠款）和奖励途径的神经成像。因此，该提议最大程度地提高了创新技术相结合的潜在科学影响，同时显着提高了它们的可行性。此外，结合了关于风险赋予基因和感应奖励缺陷的新兴数据的极端临床表型，这对于拟议的研究来说是一个令人信服的案例。为此，具体的目的是：（1）从具有健康对照和健康对照的个体中得出IPSC； （2）分析来自对照和IPSC的神经细胞的基因表达谱； （3）测试跨层次假设，例如，通过神经影像学观察到的多巴胺受体过量的神经机制，并确定赋予遗传机制对这一过程的风险贡献的贡献。多能干细胞将被驱动以分化为多巴胺能神经元，以基于我们的假设进行未来的机械探索。阐明基因之间的联系，奖励机制和饮食行为的极端具有无误的潜力，即不仅对神经性厌食症，而且对肥胖症的新兴流行也产生了机械性和治疗知识。 公共卫生相关性：神经性厌食症（AN）是一种高度可遗传的疾病，在精神病中死亡最高，但缺乏有效的治疗方法。体细胞对多能状态的遗传重编程会产生诱导的多能干细胞（IPSC），并且对供体个体具有同性基因，即它们具有相似的遗传背景。我们将比较来自对照和IPSC的神经细胞的基因表达谱，并测试风险支配遗传变异对神经元表型的贡献。