The dopamine transporter in eating disorders: Uncovering new therapeutic targets

饮食失调中的多巴胺转运蛋白：发现新的治疗靶点

基本信息

批准号：
8771759
负责人：
LYNETTE C DAWS
金额：
$ 21.68万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771759
关键词：
17 year old Acute Address Adolescence Adolescent Adult Affect Affinity Age Anorexia Attenuated Behavioral Binge Eating Biological Models Body Weight decreased Brain region Bulimia Characteristics Cocaine Complex Corpus striatum structure Data Diet Disease Dopamine Dorsal Dose Eating Eating Behavior Eating Disorders Elderly Electrochemistry Etiology Exercise Extracellular Fluid Fatty acid glycerol esters Feeding behaviors Female Female Adolescents Food Functional disorder Future Goals Homeostasis Human Hunger Hyperactive behavior Hypersensitivity Individual Injection of therapeutic agent Insulin Investigation Knowledge Measures Mental Depression Mitogen-Activated Protein Kinases Modeling Motivation Motor Activity Neurons Outcome Patients Pharmaceutical Preparations Phosphotransferases Plasma Population Protein Kinase Public Health Ramp Rattus Reading Regulation Reporting Rewards Rodent Role Severities Sex Behavior Sex Characteristics Sex Functioning Signal Transduction Therapeutic Intervention Time addiction age related base boys dopamine transporter drug of abuse effective therapy feeding food addiction girls improved in vivo insight insulin sensitivity male neurochemistry neurotransmission new therapeutic target novel prevent public health relevance response sex statistics uptake

项目摘要

DESCRIPTION (provided by applicant): Although eating disorders are complex and their etiology unclear, dysregulation of dopamine neurotransmission is a consistent finding. A vital regulator of dopamine neurotransmission is the dopamine transporter (DAT). DAT terminates dopamine neurotransmission by uptake of dopamine from extracellular fluid and because of this DAT is a primary determinant of both the strength and duration of dopamine signaling. In spite of its critical role in maintaining dopamine homeostasis, there have been no investigations of DAT function, per se, in eating disorders. Using neurochemical, cellular and behavioral approaches, we have shown that DAT activity is highly sensitive to diet and food intake, strongly supporting the notion that DAT activity is dysregulated in individuals with eating disorders. However, studies so far have been in adult, male rodents. Anorexia, bulimia and binge eating are most common in teenage girls. What is lacking in our fundamental understanding of DAT is how its activity varies as a function of age and sex and, importantly, how age and sex interact to contribute to "disordered eating". In turn, how does aberrant DAT activity contribute to "disordered eating"? Here we will begin to fill these critical knowledge gaps. We will make use of the "activity-based anorexia" (ABA) model in rats to determine how age, sex and "eating disorder" influence DAT function and how manipulations of DAT activity modify eating behavior. The ABA model recapitulates key characteristics of anorexia in humans, including reduced food intake in the presence of hunger, weight loss, hyperactivity, and increased insulin sensitivity. Importantly, in this model rats must "choose" between eating and another rewarding condition, exercise. Thus, food intake is controlled by the rat and not artificially by the experimenter, offering a powerful translational model system. We will explore phosphotidylinositol 3-kinase (PI3K) and extracellular signal-regulated protein kinase (ERK), regulators of DAT activity that we have identified as putative targets to restore normal DAT function, as novel targets for therapeutic intervention to prevent, or lessen the severity of ABA. Given the well-established role of dopamine in reward and motivation, these studies will not only provide mechanistic insight into dysregulation of dopamine neurotransmission in eating disorders, but also other illnesses, including addiction and depression, which are often co-morbid with eating disorders.

描述（由申请人提供）：尽管饮食失调很复杂，并且病因尚不清楚，但多巴胺神经传递的失调是一个一致的发现。多巴胺神经传递的重要调节剂是多巴胺转运蛋白（DAT）。 DAT通过从细胞外液中吸收多巴胺来终止多巴胺神经传递，并且由于该DAT是多巴胺信号传导强度和持续时间的主要决定因素。尽管它在维持多巴胺稳态方面具有关键作用，但在饮食失调方面，尚无对DAT功能的研究。使用神经化学，细胞和行为方法，我们表明DAT活动对饮食和食物摄入高度敏感，强烈支持饮食失调患者DAT活动失调的观念。但是，到目前为止，已经研究了成年男性啮齿动物。在十几岁的女孩中，厌食症，贪食症和暴饮暴食最为常见。我们对DAT的基本理解缺乏的是它的活动如何随着年龄和性别的函数而变化，重要的是，年龄和性别如何相互作用以促进“无序饮食”。反过来，异常的DAT活动如何导致“饮食失调”？在这里，我们将开始填补这些关键的知识差距。我们将利用大鼠中的“基于活动的厌食”（ABA）模型来确定年龄，性别和“饮食失调”如何影响DAT功能以及DAT活动的操作如何改变饮食行为。 ABA模型概括了人类厌食症的关键特征，包括在饥饿，体重减轻，多动症和胰岛素敏感性提高的情况下减少食物摄入量。重要的是，在此模型中，大鼠必须在饮食和另一个有意义的疾病之间“选择”。因此，食物摄入量由大鼠控制，而不是由实验者人为地控制，提供了强大的翻译模型系统。我们将探索磷酸丁基肌醇3-激酶（PI3K）和细胞外信号调节的蛋白激酶（ERK），这是DAT活性的调节剂，我们已将其确定为恢复正常DAT功能的假定靶标，作为恢复正常的DAT功能，作为治疗性干预的新目标，以防止ABA的严重程度或减少ABA的严重性。鉴于多巴胺在奖励和动机中的作用良好，这些研究不仅将提供有关多巴胺神经传递失调在饮食失调中的失调，而且还提供了其他疾病，包括成瘾和抑郁症，这些疾病通常与饮食障碍共处。