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RGS modulation of 5HT1A receptor signaling in depression

RGS 调节抑郁症中 5HT1A 受体信号

基本信息

批准号：
8452672
负责人：
John R. Traynor
金额：
$ 22.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-04 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452672
关键词：
8-Hydroxy-2-(di-n-propylamino)tetralin Acute Affect Agonist American Animal Model Animals Anti-Anxiety Agents Antidepressive Agents Anxiety Behavior Behavior Control Behavioral Biochemical Biological Brain region Chronic Control Animal Coupled Development Disease Dopamine Uptake Inhibitors Drug Targeting Drug usage Family Fluvoxamine G Protein-Coupled Receptor Genes GTP-Binding Protein Regulators GTP-Binding Proteins Heterotrimeric GTP-Binding Proteins Hippocampus (Brain)Individual Knock-out Knowledge Mediating Mental Depression Molecular Mood Disorders Moods Mus Mutant Strains Mice Norepinephrine Patients Pharmaceutical Preparations Phenotype Play Population Prefrontal Cortex Proteins RGS Proteins RNA Interference Receptor Activation Receptor Signaling Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Agents Signal Transduction Site Specificity Testing Translating Transmembrane Domain Work depressive symptoms improved inhibitor/antagonist mouse model novel novel strategies receptor receptor coupling receptor function receptor-mediated signaling response

项目摘要

DESCRIPTION (provided by applicant): Depression is an illness that is poorly understood and treatments are only effective in a certain percentage of the population. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant medications. SSRIs act indirectly via 5HT receptors, including the 5HT1A receptor that couples to heterotrimeric G proteins. Regulators of G protein signaling (RGS) are a family of intracellular proteins that negatively modulate receptor-mediated G protein signaling. Using mutant mice we have identified a subset of 5HT1A receptors coupled to G?i2 and negatively regulated by RGS proteins that appear to mediate the beneficial actions of SSRIs. This led us to consider that RGS protein modulation of 5HT1A receptor signaling may play an important role in depression and so present a novel target for the treatment of depression. However, there are >20 mammalian RGS proteins and a general inhibitor will likely have a broad range of effects. In this proposal we seek to identify the specific RGS protein that modulates 5HT1A receptors and therefore controls behavioral responses to 5HT1A receptor activation related to mood disorders. The proposed work will use a combination of behavioral, biochemical and molecular biological approaches to provide knowledge of RGS proteins in serotonin signaling in animal models of depression and implicate RGS proteins as drug targets to promote the antidepressant actions of currently available SSRI's without enhancing their unwanted effects.

描述(申请人提供)：抑郁症是一种知之甚少的疾病，治疗只对一定比例的人群有效。选择性5-羟色胺再摄取抑制剂(SSRI)是最常用的抗抑郁药物。SSRI通过5-羟色胺受体间接发挥作用，包括与异源三聚体G蛋白偶联的5-HT1A受体。G蛋白信号调节因子(RGS)是一类细胞内蛋白家族，对受体介导的G蛋白信号进行负向调节。利用突变小鼠，我们已经鉴定了5HT1A受体的一个子集，该受体与G？I2偶联，并受到RGS蛋白的负调控，这些蛋白似乎介导了SSRIs的有益行为。这使得我们认为RGS蛋白对5HT1A受体信号的调节可能在抑郁症中发挥重要作用，从而为抑郁症的治疗提供了一个新的靶点。然而，哺乳动物中有20种RGS蛋白，一种通用的抑制剂可能会产生广泛的影响。在这项建议中，我们试图确定特定的RGS蛋白，它调节5HT1A受体，从而控制与情绪障碍相关的5HT1A受体激活的行为反应。这项拟议的工作将结合行为、生化和分子生物学方法，在抑郁症动物模型中提供关于RGS蛋白质在5-羟色胺信号转导中的知识，并将RGS蛋白质作为药物靶点，以促进现有SSRI的抗抑郁作用，同时不增强它们不想要的影响。