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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

基本信息

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
项目类别：
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

项目摘要

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