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.

项目摘要 本研究的目的是探讨κ阿片受体（KOR）在神经病理学中的作用 边缘型人格障碍（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，一般人群中高达33%的自杀死亡可归因于 波士顿警局更复杂的是，研究表明，在BPD方面存在显着的性别差异， 症状表现和神经生物学; BPD男性有较高的自杀风险，但获得有效治疗的机会较少。 治疗尽管如此，现有的治疗方法在很大程度上不能解决整体BPD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 和网络的改变，并有相关的结构差异和失调，在额叶边缘 BPD发生率和症状严重程度增加的区域回路，以及BPD中的自杀行为。 研究BPD症状的分子机制，特别是自杀风险，是一项重要的研究。 重要的下一步是促进新治疗的开发和促进BPD的风险预防。 新出现的证据表明KOR与BPD和自杀行为有关。KOR在情绪中起着关键作用 调节，社会功能和冲动-所有这些都是BPD的核心，并与自杀风险有关。 尸检研究表明KOR与自杀死亡之间存在关联。此外，各种 在动物和人类中的研究已经表明KOR拮抗剂可以产生抗抑郁药，抗焦虑药， 甚至还有抗自杀的作用，尽管研究也表明男性和女性对这种作用的反应可能不同。 剂.重要的是，相对于滥用药物，KOR药物对多巴胺的影响是适度的， 滥用的可能性基于使用相同技术的新导频数据的支持，我们现在提出了一种 使用正电子技术对BPD患者相对于健康成人（HA）的KOR可用性进行的新研究 放射性断层扫描（PET），一种脑成像技术，和放射性配体[11 C]EKAP，其选择性结合至 大脑中的KOR（目标1a）。我们还将评估KOR可用性和SA历史之间的关联， BPD（目标1b）。接下来，我们将评估冲动、情绪失调和BPD之间的关系 症状严重程度-与预后和自杀风险相关的关键内在表型，以及对治疗的抵抗力-以及 KOR在BPD的可用性（目标2）。最后，我们将评估BPD和HA中KOR可用性的性别差异。 这项研究的结果将提供潜在的关键洞察这种新的分子之间的关系， 目标、BPD症状表现和自杀行为根据调查结果，我们将寻求资金， PET研究旨在测试潜在的非成瘾性KOR靶向药物，用于总体BPD症状减轻， 和自杀风险。