Building Translational Research in Obsessive-Compulsive Disorder (R24)

建立强迫症的转化研究（R24）

• 批准号: 7347111
• 负责人: HELEN BLAIR SIMPSON
• 金额: $ 32.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-06 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7347111
• 关键词: Acute; Affect; Aftercare; Agonist; Animal Model; Animals; Behavior; Brain; Brain region; Characteristics; Chronic; Clinical; Clinical Trials; Clomipramine; Corpus striatum structure; Coupling; Data; Desipramine; Fluoxetine; Foundations; Functional disorder; Funding; Future; Genetic; Globus Pallidus; Glutamates; Goals; Human; Laboratories; Lead; Life; Literature; Localized; Measures; Mental Health; Mental disorders; Mission; Molecular; Monoclonal Antibody R24; Mus; Neurobiology; Norepinephrine; Obsessive-Compulsive Disorder; Patients; Pharmaceutical Preparations; Population; Process; Property; Public Health; Reporting; Research Personnel; Resources; Role; Scientific Advances and Accomplishments; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1B; Serotonin Receptor 5-HT2A; Specificity; Substantia nigra structure; Symptoms; System; Techniques; Testing; Thalamic structure; Transgenic Mice; Translational Research; Week; Work; brain pathway; disability; frontal lobe; human study; improved; inhibitor/antagonist; locomotor deficit; mouse model; neuroimaging; novel; prepulse inhibition; prevent; programs; receptor; receptor expression; response; reuptake; severe mental illness; stereotypy; translational approach; translational study; zolmitriptan

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a severe mental disorder that is a significant public health problem. The neurobiology of OCD remains unclear because it is difficult to study brain pathways in living people, and neither post-mortem studies nor validated animal models exist. We propose to build a novel partnership between basic and clinical researchers to develop animal models of specific neurobiological features of OCD that can guide future human studies. Our ultimate goal is to elucidate the neurobiology of OCD and to spearhead novel treatment approaches. This R24 application will enable us to develop the laboratory and scientific resources to be able to conduct this type of translational work. As a first step, we will examine the role of sensorimotor gating deficits and the 5-HT1B receptor (known as the 5-HT1DJ3 receptor in the human literature), which have both been implicated in OCD. Our preliminary findings in mice indicate that acute 5-HT1B agonist challenge leads to sensorimotor gating deficits as measured by decreased prepulse inhibition (PPI) and repetitive behavior (i.e., locomotor stereotypy); these effects are blocked by chronic pretreatment with the serotonin reuptake inhibitor (SRI) fluoxetine. OCD patients may also have PPI deficits and do have repetitive behavior. This R24 will enable us to develop the resources needed to test the working hypothesis that increased 5-HT1B function leads to PPI deficits and locomotor stereotypy in mice and may contribute to the PPI deficits and repetitive behavior in OCD. Specifically, we will: 1) generate transgenic mice with human 5-HT1B receptors; 2) examine in these mice the effects of OCD treatments on the behaviors induced by 5-HT1B agonists (decreased PPI and locomotor stereotypy) and on 5-HT1B receptor expression and functional coupling in the brain; and 3) examine whether PPI deficits in OCD patients are associated with clinical features and/or SRI treatment response. In the process, we will lay the foundation for future translational research on other aspects of the serotonin system as they relate to the neurocircuitry of OCD. We expect that our work will lead to a collaborative R01 or Translational Research Center application that will integrate animal and human work in the quest for novel treatments to reduce the burden of OCD. Thus, our application is directly relevant to NIMH's mission: to improve mental health by advancing the scientific understanding of a severe mental illness like OCD.

描述（由申请人提供）：强迫症（OCD）是一种严重的精神障碍，是一个重大的公共卫生问题。强迫症的神经生物学仍不清楚，因为很难研究活人的大脑通路，而且既不存在尸检研究，也不存在经过验证的动物模型。我们建议在基础研究人员和临床研究人员之间建立新型合作伙伴关系，开发具有强迫症特定神经生物学特征的动物模型，以指导未来的人类研究。我们的最终目标是阐明强迫症的神经生物学并引领新的治疗方法。该 R24 应用程序将使我们能够开发实验室和科学资源，以便能够进行此类转化工作。第一步，我们将研究感觉运动门控缺陷和 5-HT1B 受体（在人类文献中称为 5-HT1DJ3 受体）的作用，这两者都与强迫症有关。我们在小鼠中的初步研究结果表明，急性 5-HT1B 激动剂挑战会导致感觉运动门控缺陷，具体表现为前脉冲抑制 (PPI) 和重复行为（即运动刻板性）的降低；使用血清素再摄取抑制剂（SRI）氟西汀进行长期预处理可以阻断这些作用。强迫症患者也可能有 PPI 缺陷，并且确实有重复行为。 R24 将使我们能够开发所需的资源来测试工作假设，即 5-HT1B 功能增加会导致小鼠 PPI 缺陷和运动定型，并可能导致强迫症中的 PPI 缺陷和重复行为。具体来说，我们将：1）产生具有人类5-HT1B受体的转基因小鼠； 2) 在这些小鼠中检查强迫症治疗对 5-HT1B 激动剂诱导的行为（降低 PPI 和运动定型）以及大脑中 5-HT1B 受体表达和功能耦合的影响； 3) 检查 OCD 患者的 PPI 缺陷是否与临床特征和/或 SRI 治疗反应相关。在此过程中，我们将为未来对血清素系统其他方面的转化研究奠定基础，因为它们与强迫症的神经回路有关。我们预计我们的工作将促成 R01 或转化研究中心的协作应用程序，该应用程序将整合动物和人类的工作，寻求新的治疗方法，以减轻强迫症的负担。因此，我们的应用程序与 NIMH 的使命直接相关：通过增进对强迫症等严重精神疾病的科学认识来改善心理健康。