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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：
8283884
负责人：
John R. Traynor
金额：
$ 19.44万
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8283884
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 Delivery Systems 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. PUBLIC HEALTH RELEVANCE: Depression is a poorly understood illness that affects approximately 10 million Americans. Moreover, treatments for depression are ineffective in a majority of patients. We have recently identified a family of intracellular proteins (RGS proteins) that appear to enhance the beneficial actions of selective serotonin reuptake inhibitors (SSRIs) which are the major drugs used for the treatment of depression. In this proposal we seek to identify the particular RGS protein(s) involved and so identify a novel target for treatment of depressive illness.

描述（由申请人提供）：抑郁症是一种人们知之甚少的疾病，治疗仅在一定比例的人群中有效。选择性5-羟色胺再吸收抑制剂（SSRI）是最常用的抗抑郁药物。SSRIs通过5 HT受体间接起作用，包括与异源三聚体G蛋白偶联的5 HT 1A受体。G蛋白信号调节因子（Regulators of G protein signaling，RGS）是一类负性调节受体介导的G蛋白信号转导的细胞内蛋白。使用突变小鼠，我们已经确定了一个子集的5 HT 1A受体耦合到G？i2和负调控的RGS蛋白，似乎介导SSRIs的有益作用。这使我们认为RGS蛋白对5 HT 1A受体信号的调节可能在抑郁症中起重要作用，因此为抑郁症的治疗提供了一个新的靶点。然而，存在>20种哺乳动物RGS蛋白，并且一般抑制剂将可能具有广泛的影响。在这个建议中，我们试图确定特定的RGS蛋白，调节5 HT 1A受体，因此控制行为反应的5 HT 1A受体激活相关的情绪障碍。拟议的工作将使用行为，生物化学和分子生物学方法的组合，以提供RGS蛋白在抑郁症动物模型中的5-羟色胺信号传导的知识，并暗示RGS蛋白作为药物靶点，以促进目前可用的SSRI的抗抑郁作用，而不会增强其不必要的作用。抑郁症是一种人们知之甚少的疾病，影响着大约1000万美国人。此外，抑郁症的治疗对大多数患者无效。我们最近发现了一个细胞内蛋白家族（RGS蛋白）这似乎增强了选择性5-羟色胺再摄取抑制剂（SSRI）的有益作用，SSRI是用于治疗抑郁症的主要药物。在这项提案中，我们试图确定特定的RGS蛋白（S）参与，从而确定一个新的目标，用于治疗抑郁症。