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通信。从一个神经元中分泌的神经递质在其他细胞的膜上结合特定受体，并在这些细胞中引起一系列反应。多巴胺是一种神经递质，可调节各种各样的生物学过程，包括认知和情感，动机和奖励，运动以及某些激素的释放。多巴胺系统中的失衡已与精神分裂症，躁郁症，注意力缺陷多动障碍，图雷特综合症，成瘾，帕金森氏病和高血压等多种疾病有关。哺乳动物的基因组编码五种不同的多巴胺受体，这些受体可以根据其细胞信号传导和序列同源性分为两类。各种类型的受体被认为介导了不同的生物学功能，并与不同的疾病有关。两类多巴胺受体也可以在药理学上进行区分，但是这种歧视不是绝对的。此外，很难在同一类中的药理学区分药理。给定的药物通常作用于多种受体，从而产生不良的副作用。因此，具有高度特异性的各种多巴胺受体的药物对于成功治疗涉及特定多巴胺受体类型的疾病至关重要。由于许多神经元表达多种多巴胺受体，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，我们提出了一种新型的分子方法，可以选择性地记录鼠大脑中特定多巴胺受体亚型的激活。由于我们的系统具有极高的选择性，因此可以明确地确定针对给定药物的特定神经元中激活了哪种受体亚型。无论该神经元中其他种类的多巴胺受体的存在如何，都可以完成这项工作。我们将生成的动物模型将使副作用更少的特定药物开发和测试。此外，我们的技术可用于识别小鼠模型中特定电路中的变化，例如精神分裂症和帕金森氏病，提供了有关这些疾病进展的机制的线索。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，因此可以很容易地适应其他受体。因此，一种在动物模型中选择性监测特定受体激活的方法将对生物医学研究界非常广泛的部分产生重大影响。我们建议生成一种新型的分子方法，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，例如精神分裂症，躁郁症，注意力缺陷多动障碍，图雷特综合症，成瘾，帕金森氏病和高血压。这种动物模型的可用性将使更具特异性的多巴胺受体激动剂和拮抗剂的发展和测试具有更少的副作用。