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.

项目总结 本研究的目的是探讨kappa阿片受体(Kor)在症状学中的作用。 临界性人格障碍(BPD)，这是一种与自杀风险惊人地增加相关的疾病 自杀未遂(SA；高达75%)和自杀(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 转到BPD。增加复杂性的是，研究表明，BPD在这两个方面都存在显著的性别差异 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，可用的治疗方法在很大程度上不能解决整个bpd症状。 严重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，并与额叶边缘的结构差异和调节失调相关 BPD发生率和症状严重程度增加的区域环路，以及BPD的自杀行为。 研究引起BPD症状的分子机制，特别是自杀风险，是一个 至关重要的下一步，既要促进新疗法的开发，又要促进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 监管、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，各种不同的 在动物和人类身上的研究表明，KOR拮抗剂可以产生抗抑郁、抗焦虑、 甚至还有抗自杀的作用，尽管研究也表明男性和女性对此的反应可能不同 探员们。重要的是，与滥用药物相比，KOR特工对多巴胺的影响不大，从而减少了人们的担忧 关于滥用的可能性。基于使用相同技术的新的导频数据的支持，我们现在提出一种 用正电子技术研究BPD患者相对于健康成人(HA)的KOR可用性 发射断层扫描(PET)，一种脑成像技术，以及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之间的联系。 症状严重程度-与预后和自杀风险有关的关键内表型，以及对治疗的抵抗-以及 Kor可用性(BPD)(目标2)。最后，我们将评估在BPD和HA中KOR可用性的性别差异。 这项研究的结果将为了解这种新分子之间的关系提供潜在的关键见解 目标、BPD症状表现和自杀行为。根据调查结果，我们将寻求更大规模的资金 测试潜在的非成瘾性KOR靶向药物对总体BPD症状缓解的PET研究， 和自杀风险。