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且病因尚不清楚，但多巴胺神经传递失调是一致的发现。多巴胺神经传递的重要调节剂是多巴胺转运蛋白（DAT）。 DAT 通过从细胞外液中摄取多巴胺来终止多巴胺神经传递，因此 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 DAT 在维持多巴胺稳态方面发挥着关键作用，但目前尚未对 DAT 功能本身在饮食失调中的作用进行研究。使用神经化学、细胞和行为方法，我们发现 DAT 活性对饮食和食物摄入高度敏感，有力地支持了饮食失调个体中 DAT 活性失调的观点。然而，迄今为止的研究都是针对成年雄性啮齿动物。厌食症、贪食症和暴食症在少女中最常见。我们对 DAT 的基本理解缺乏的是它的活性如何随着年龄和性别的变化而变化，更重要的是，年龄和性别如何相互作用导致“饮食失调”。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空白。我们将利用大鼠的“基于活动的厌食症”（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 活动的操纵如何改变饮食行为。 ABA 模型概括了人类厌食症的关键特征，包括饥饿时食物摄入量减少、体重减轻、多动和胰岛素敏感性增加。重要的是，在这个模型中，老鼠必须在进食和另一种奖励条件（运动）之间“选择”。因此，食物摄入量是由老鼠控制的，而不是由实验者人为控制的，这提供了一个强大的转化模型系统。我们将探索磷脂酰肌醇 3 激酶 (PI3K) 和细胞外信号调节蛋白激酶 (ERK)，它们是 DAT 活性的调节因子，我们已将其确定为恢复正常 DAT 功能的推定靶标，并将其作为治疗干预的新靶标，以预防或减轻 DAT 活性。 ABA 的严重程度。鉴于多巴胺在奖励和动机中的明确作用，这些研究不仅将为饮食失调中多巴胺神经传递失调提供机制见解，而且还将提供其他疾病，包括成瘾和抑郁症，这些疾病通常与饮食失调共存。