in vivo investigation of KOR as a marker of BPD and suicide related endophenotypes

KOR 作为 BPD 和自杀相关内表型标志物的体内研究

• 批准号: 10735604
• 负责人: Margaret Taylor Davis
• 金额: $ 80.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-20 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735604
• 关键词: Address; Adult; Affect; Affective; Aggressive behavior; Animals; Anti-Anxiety Agents; Antidepressive Agents; Area; Attention; Autopsy; Binding; Borderline Personality Disorder; Brain; Brain imaging; Chronic; Chronic stress; Clinical; Clinical Trials; Data; Depressed mood; Development; Diagnostic; Disease; Dissociation; Distress; Dopamine; Down-Regulation; Dynorphins; Functional disorder; Funding; Future; General Population; Goals; Human; Hydrocortisone; Imaging Techniques; Impaired cognition; Impulsivity; Incidence; Individual; Insula of Reil; Intervention; Investigation; Life; Link; Low Prevalence; Magnetic Resonance Imaging; Molecular; Molecular Target; Morbidity - disease rate; Neurobiology; Opioid; Opioid Antagonist; Opioid Peptide; Pain; Participant; Peripheral; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Prevention; Prognosis; Recording of previous events; Regulation; Research; Resistance; Risk; Risk Reduction; Role; Self-Injurious Behavior; Serotonin; Severities; Sex Differences; Social Functioning; Stress; Suicide; Suicide attempt; Symptoms; System; Techniques; Testing; Treatment outcome; Underserved Population; Woman; Work; abuse liability; beta-Endorphin; clinically relevant; disorder risk; drug of abuse; effective therapy; emotion dysregulation; emotion regulation; endogenous opioids; endophenotype; epidemiology study; experience; falls; high risk; high risk population; imaging study; in vivo; innovation; insight; kappa opioid receptors; male; men; mortality; mu opioid receptors; novel; opioid mortality; pain perception; pharmacologic; pre-clinical; preclinical study; psychiatric symptom; radioligand; radiotracer; receptor expression; receptor-mediated signaling; reduce symptoms; reducing suicide; response; sex; social; stress related disorder; suicidal; suicidal behavior; suicidal morbidity; suicidal risk; suicide mortality; symptom treatment; symptomatology; targeted agent; therapy development; treatment risk

PROJECT SUMMARY The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide attempt (SA; up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%), epidemiological research has shown that up to 33% of suicide deaths in the general population are attributable to BPD. Adding complexity, research suggests that significant sex differences exist in BPD with respect to both symptoms’ presentation and neurobiology; BPD males have higher suicide risk, but less access to effective treatment. Despite this, available treatments are largely not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging (MRI) studies have identified structural and network alterations in BPD and have associated structural differences and dysregulation in a frontolimbic circuit of regions with incidence of BPD and increased symptom severity, and suicidal behavior in BPD. Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically, is an essential next step to both promote development of novel treatments and facilitate risk prevention in BPD. Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion regulation, social functioning, and impulsivity– all of which are both central to BPD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of studies in both animals and humans have shown that KOR antagonists can produce antidepressant, anxiolytic, and even anti-suicidal effects, though research also suggests men and women may respond differently to such agents. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Based on support from novel pilot data using the same techniques, we now propose a novel investigation of KOR availability in individuals with BPD relative to healthy adults (HA) using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1a). We will also evaluate the association between KOR availability and SA history in BPD (Aim 1b). Next, we will evaluate the association between impulsivity, emotion dysregulation, and BPD symptom severity – key endophenotypes related to prognosis and suicide risk and resistant to treatment – and KOR availability in BPD (Aim 2). Finally, we will evaluate sex differences in KOR availability in BPD and HA. Results of this study will provide potentially critical insight into the relationship between this novel molecular target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction, and suicide risk.

项目概要 本研究的目的是调查 kappa 阿片受体 (KOR) 在症状学中的作用 边缘性人格障碍（BPD），一种与自杀风险惊人升高相关的疾病 自杀未遂（SA；高达 75%）和自杀死亡（高达 10%）。尽管 BPD 的患病率相对较低（1-5%）， 流行病学研究表明，普通人群中高达 33% 的自杀死亡归因于自杀 到 BPD。研究表明，BPD 中存在显着的性别差异，这增加了复杂性。 症状表现和神经生物学； BPD 男性自杀风险较高，但获得有效治疗的机会较少 治疗。尽管如此，现有的治疗方法很大程度上无法解决 BPD 的整体症状 严重程度或迅速降低自杀风险。磁共振成像（MRI）研究已经确定了结构 和 BPD 中的网络改变，并与额边缘的结构差异和失调相关 BPD 发病率和症状严重程度增加的区域的循环，以及 BPD 中的自杀行为。 研究造成 BPD 症状、特别是自杀风险的分子机制是一项重要的研究工作。 下一步是促进新型治疗方法的开发和促进 BPD 风险预防的重要一步。 新出现的证据表明 KOR 与 BPD 和自杀行为有关。 KOR 在情感中发挥着关键作用 调节、社会功能和冲动——所有这些都是 BPD 的核心，并且与自杀风险相关。 尸检研究表明 KOR 与自杀死亡之间存在关联。此外，各种 对动物和人类的研究表明，KOR 拮抗剂可以产生抗抑郁、抗焦虑、 甚至还有抗自杀作用，尽管研究也表明男性和女性对此的反应可能不同 代理。重要的是，与滥用药物相比，KOR 药物对多巴胺的影响较小，从而减少了担忧 关于滥用的可能性。基于使用相同技术的新颖试点数据的支持，我们现在提出了 使用正电子对 BPD 患者相对于健康成人 (HA) 的 KOR 可用性进行新研究 发射断层扫描 (PET)（一种脑成像技术）和选择性结合的放射性配体 [11C]EKAP 大脑中的 KOR（目标 1a）。我们还将评估 KOR 可用性与 SA 历史记录之间的关联 BPD（目标 1b）。接下来，我们将评估冲动、情绪失调和 BPD 之间的关联 症状严重程度——与预后、自杀风险和治疗耐药相关的关键内表型——以及 BPD 中的 KOR 可用性（目标 2）。最后，我们将评估 BPD 和 HA 中 KOR 可用性的性别差异。 这项研究的结果将为这种新型分子之间的关系提供潜在的重要见解。 目标、BPD 症状表现和自杀行为。根据调查结果，我们将为更大的项目寻求资金 PET 研究旨在测试潜在的非成瘾性 KOR 靶向药物，以减少整体 BPD 症状， 和自杀风险。