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，治疗方法仅对一定比例的人群有效。选择性血清素再摄取抑制剂（SSRI）是最常用的抗抑郁药物。 SSRIs 通过 5HT 受体（包括与异三聚体 G 蛋白偶联的 5HT1A 受体）间接发挥作用。 G 蛋白信号传导调节剂 (RGS) 是一个细胞内蛋白家族，可负向调节受体介导的 G 蛋白信号传导。使用突变小鼠，我们鉴定了与 G?i2 偶联并受 RGS 蛋白负调节的 5HT1A 受体子集，这些受体似乎介导 SSRI 的有益作用。这使我们认为 RGS 蛋白对 5HT1A 受体信号传导的调节可能在抑郁症中发挥重要作用，因此为抑郁症的治疗提供了一个新的靶点。然而，哺乳动物 RGS 蛋白有超过 20 种，一般抑制剂可能会产生广泛的作用。在本提案中，我们试图鉴定调节 5HT1A 受体的特定 RGS 蛋白，从而控制与情绪障碍相关的 5HT1A 受体激活的行为反应。拟议的工作将结合行为、生化和分子生物学方法，提供抑郁症动物模型中血清素信号传导中 RGS 蛋白的知识，并将 RGS 蛋白作为药物靶点，以促进现有 SSRI 的抗抑郁作用，而不增强其不良作用。。公共卫生相关性：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来说是无效的。我们最近鉴定了一个细胞内蛋白家族（RGS 蛋白）似乎可以增强选择性血清素再摄取抑制剂（SSRI）的有益作用，而选择性血清素再摄取抑制剂是治疗抑郁症的主要药物。在本提案中，我们试图确定所涉及的特定 RGS 蛋白，从而确定治疗抑郁症的新靶点。