A Molecular Method to Selectively Record Activation of Dopamine Receptor Subtypes

选择性记录多巴胺受体亚型激活的分子方法

• 批准号: 7904086
• 负责人: Gilad Barnea
• 金额: $ 28.32万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904086
• 关键词: Address; Adverse effects; Animal Model; Attention deficit hyperactivity disorder; Binding; Biological Process; Biomedical Research; Bipolar Disorder; Brain; Cells; Chemicals; Cognition; Communities; Development; Discrimination; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dopamine Receptor; Emotions; Family; Gilles de la Tourette syndrome; Hormones; Hypertension; Knowledge; Locomotion; Mediating; Membrane; Methods; Molecular; Monitor; Motivation; Mus; Neurons; Neurotransmitters; Parkinson Disease; Peptide Signal Sequences; Pharmaceutical Preparations; Rewards; Schizophrenia; Sequence Homology; Signal Transduction; System; Technology; Testing; Translating; addiction; base; dopamine system; human disease; mammalian genome; mouse model; novel; receptor; response

Neurons communicate with one another by secreting chemical signals called neurotransmitters. The neurotransmitters secreted from one neuron bind specific receptors on the membranes of other cells and elicit a cascade of responses in these cells. Dopamine is a neurotransmitter that regulates a diverse array of biological processes including cognition and emotion, motivation and reward, locomotion, and the release of certain hormones. Imbalances in the dopamine system have been implicated in disorders as diverse as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease, and hypertension. The mammalian genome encodes five different receptors for dopamine that can be grouped into two classes based on their cellular signaling and sequence homology. The various types of receptors are thought to mediate different biological functions and are implicated in different disorders. The two classes of dopamine receptors can also be distinguished pharmacologically, but this discrimination is not absolute. Furthermore, it is much more difficult to distinguish pharmacologically between receptors within the same class. A given drug often acts on multiple receptors, producing unwanted side effects. Thus, having highly specific drugs for the various dopamine receptors is critical for the successful treatment of a disorder that involves a particular dopamine receptor type with minimal side effects. Since many neurons express multiple types of dopamine receptors, it is currently impossible to attribute the effects of a particular drug to a specific receptor. Clinically, this gap of knowledge translates into an inability to predict and address the side effects of a given drug. Here we present a novel molecular method to selectively record activation of a particular dopamine receptor subtype in the murine brain. Since our system is extremely selective, it can be used to unequivocally determine which receptor subtype has been activated in a particular neuron in response to a given drug. This is accomplished regardless of the presence of other kinds of dopamine receptors in this neuron. The animal models that we will generate will enable the development and testing of specific drugs with fewer side effects. Moreover, our technology can be used to identify changes that occur in particular circuits in mouse models for human diseases such as schizophrenia and Parkinson's disease, providing clues regarding the mechanisms underlying the progression of these diseases. Finally, the current inability to monitor the activation of a particular receptor subtype also applies to other families of receptors. Since our system is modular, it can be readily adapted to study other receptors. A method to selectively monitor activation of specific receptors in an animal model will thus have a major impact on a very broad segment of the biomedical research community. We are proposing to generate a novel molecular method to selectively record the activation of a particular dopamine receptor subtype in an animal model. The dopamine system has been implicated in multiple disorders such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease and hypertension. The availability of such animal models will enable the development and testing of much more specific dopamine receptor agonists and antagonists with fewer side effects.

神经元通过分泌称为神经递质的化学信号相互交流。从一个神经元分泌的神经递质与其他细胞膜上的特定受体结合，并在这些细胞中引起级联反应。多巴胺是一种神经递质，调节各种生物过程，包括认知和情感，动机和奖励，运动以及某些激素的释放。多巴胺系统中的不平衡已经牵涉到各种各样的疾病，如精神分裂症、双相情感障碍、注意缺陷多动障碍、图雷特综合征、成瘾、帕金森病和高血压。哺乳动物基因组编码五种不同的多巴胺受体，根据它们的细胞信号传导和序列同源性可以分为两类。各种类型的受体被认为介导不同的生物学功能，并涉及不同的疾病。这两类多巴胺受体也可以区分开来，但这种区分不是绝对的。此外，区分同一类别内的受体之间的差异要困难得多。一种特定的药物通常作用于多种受体，产生不必要的副作用。因此，具有针对各种多巴胺受体的高度特异性的药物对于成功治疗涉及特定多巴胺受体类型的疾病具有最小的副作用至关重要。由于许多神经元表达多种类型的多巴胺受体，因此目前不可能将特定药物的作用归因于特定受体。在临床上，这种知识的差距转化为无法预测和解决给定药物的副作用。在这里，我们提出了一种新的分子方法来选择性地记录激活一个特定的多巴胺受体亚型在小鼠大脑。由于我们的系统具有极强的选择性，它可以用来明确地确定哪种受体亚型在特定的神经元中被激活以响应给定的药物。这一过程与该神经元中是否存在其他类型的多巴胺受体无关。我们将产生的动物模型将使开发和测试具有更少副作用的特定药物成为可能。此外，我们的技术可用于识别精神分裂症和帕金森病等人类疾病小鼠模型中特定回路发生的变化，为这些疾病的进展机制提供线索。最后，目前无法监测特定受体亚型的激活也适用于其他受体家族。由于我们的系统是模块化的，它可以很容易地适应于研究其他受体。因此，在动物模型中选择性监测特定受体活化的方法将对生物医学研究界的非常广泛的部分产生重大影响。我们建议产生一种新的分子方法，以选择性地记录动物模型中特定多巴胺受体亚型的激活。多巴胺系统与多种疾病有关，如精神分裂症、双相情感障碍、注意缺陷多动障碍、图雷特综合征、成瘾、帕金森病和高血压。这种动物模型的可用性将使得能够开发和测试具有更少副作用的更特异性的多巴胺受体激动剂和拮抗剂。