Dysregulation in mGluR5 as a marker of BPD and suicide related endophenotypes

mGluR5 失调作为 BPD 和自杀相关内表型的标志

• 批准号: 9582281
• 负责人: Margaret Taylor Davis
• 金额: $ 19.67万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9582281
• 关键词: Address; Affect; Aggressive behavior; Amygdaloid structure; Anterior; Area; Attenuated; Autopsy; Behavioral; Biological Markers; Borderline Personality Disorder; Brain region; Clinical; Cognitive; Data; Data Analyses; Development; Development Plans; Disease; Emotional; Environment; Executive Dysfunction; Exhibits; Functional disorder; Genes; Glutamatergic Agents; Glutamates; Goals; Image; Imaging Techniques; Impulsivity; Individual; Insula of Reil; Intervention; Investigation; Lead; Life; Link; Low Prevalence; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Metabotropic Glutamate Receptors; Molecular; Molecular Target; National Institute of Mental Health; Neurobiology; Neurotransmitters; Pain; Pain Threshold; Participant; Pathology; Pharmaceutical Preparations; Pharmacology; Play; Population; Positioning Attribute; Positron-Emission Tomography; Prevention; Public Health; Quality of life; Recording of previous events; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Savings; Scientist; Self-Injurious Behavior; Severities; Source; Statistical Data Interpretation; Strategic Planning; Suicide; Suicide attempt; Suicide prevention; Symptoms; System; Time; Training; Training Activity; Underserved Population; base; career; career development; cingulate cortex; clinical risk; data acquisition; design; emotion dysregulation; emotion regulation; endophenotype; epidemiology study; executive function; experience; falls; hands on research; high risk; high risk population; imaging study; improved; in vivo; innovation; insight; interest; medical schools; metabotropic glutamate receptor 5; molecular imaging; mortality; neurochemistry; neuroimaging; novel; pain perception; radioligand; reducing suicide; research and development; response; responsible research conduct; social; suicidal; suicidal behavior; suicidal morbidity; suicidal risk; suicide mortality; symptomatology; targeted biomarker; targeted treatment; therapy development; trait

This mentored clinical scientist research and career development proposal is designed to provide the candidate advanced training, expert mentoring, and hands-on research experience to facilitate development of an academic research career. The candidate’s primary goal is to become an independent molecular imaging researcher studying the neurobiology of suicide in high-risk populations. To achieve that goal, we present a comprehensive 5-year plan designed to provide rigorous training in four key areas: 1) design and conduct of PET research in high-risk clinical populations; 2) PET data acquisition and analysis; and 3) advanced statistical analysis; 4) responsible conduct of research. This proposal will be completed in a diverse, cutting edge scientific environment (Yale School of Medicine). We further propose conduct of a novel research project using molecular imaging techniques in a uniquely high-risk population: borderline personality disorder (BPD). BPD is a devastating psychiatric condition with alarmingly elevated risk for suicide attempt (up to 75%) and mortality (up to 10%). Despite BPD’s relatively low prevalence (1-3%), two recent epidemiological studies reported that more than two thirds of recent suicide attempts occurred in individuals with BPD. Unfortunately, most of the available treatments are not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging studies have enhanced our understanding of BPD pathophysiology, implicating a network of frontal (dlPFC, OFC, ACC), and limbic (amygdala, insula) regions in BPD symptom presentation. However, investigation of molecular mechanisms subserving BPD pathophysiology and suicidal behavior is an essential next step to both promote development of novel treatments and facilitate risk prevention in this population. Emerging evidence implicates the metabotropic glutamate 5 receptor (mGluR5) in BPD and suicidal behavior. mGlur5 plays critical roles in emotion regulation and pain perception which are both central to BPD pathology and related to suicide risk. Further, genes associated with mGluR5 are linked to suicide attempt and mortality. Our exciting pilot data in individuals with BPD (n=7) shows higher mGluR5 availability in fronto-llimbic brain regions linked BPD pathophysiology, with large magnitude differences in those who attempted suicide in the past. We therefore propose to confirm and extend initial findings by investigating mGluR5 availability in vivo in BPD using PET and the highly-selective radioligand [18F]FPEB (Aim 1), evaluating the potential role of mGluR5 as a biomarker for suicide attempt in BPD (Aim 2), and examining the relationship between suicide and BPD-related behavioral endophenotypes and mGluR5 availability (Aim 3). Results of this study will provide potentially critical insight into the relationship between this novel molecular target and symptomatology of BPD. Completion of the proposed training plan and research project will optimally position the candidate to develop a career as a molecular imaging researcher capable of meaningfully contributing to suicide prevention efforts.

这项受指导的临床科学家研究和职业发展提案旨在提供 候选人高级培训、专家指导和实践研究经验，以促进发展 学术研究生涯。候选人的首要目标是成为一名独立的分子影像专家 研究高危人群自杀神经生物学的研究人员。为了实现这一目标，我们提出了 全面的 5 年计划，旨在在四个关键领域提供严格的培训：1) 设计和实施 高危临床人群的PET研究； 2）PET数据采集与分析； 3）高级统计 分析; 4) 负责任地进行研究。该提案将以多元化、前沿的方式完成 科学环境（耶鲁大学医学院）。我们进一步建议利用 分子成像技术在独特的高危人群中的应用：边缘型人格障碍（BPD）。 BPD 是一种毁灭性的精神疾病，自杀企图的风险惊人地升高（高达 75%），并且 死亡率（高达 10%）。尽管 BPD 的患病率相对较低（1-3%），但最近的两项流行病学研究 报道称，近期超过三分之二的自杀未遂事件发生在边缘性人格障碍患者身上。很遗憾， 大多数可用的治疗方法无法解决整体 BPD 症状的严重程度或快速解决 降低自杀风险。磁共振成像研究增强了我们对 BPD 的理解 病理生理学，涉及额叶（dlPFC、OFC、ACC）和边缘（杏仁核、岛叶）区域的网络 BPD 症状表现。然而，对促进 BPD 的分子机制的研究 病理生理学和自杀行为是促进新型药物开发的重要下一步 治疗并促进该人群的风险预防。 新证据表明代谢型谷氨酸 5 受体 (mGluR5) 与 BPD 和自杀倾向有关 行为。 mGlur5 在情绪调节和疼痛感知中发挥关键作用，这两者都是 BPD 的核心 病理学与自杀风险相关。此外，与 mGluR5 相关的基因与自杀企图和 死亡。我们在 BPD 患者 (n=7) 中进行的令人兴奋的试验数据显示，额叶边缘的 mGluR5 可用性更高 大脑区域与 BPD 病理生理学相关，在尝试自杀的人中存在巨大差异 过去。因此，我们建议通过调查 mGluR5 体内可用性来确认和扩展初步发现 在 BPD 中使用 PET 和高选择性放射性配体 [18F]FPEB（目标 1），评估 mGluR5 作为 BPD 自杀未遂的生物标志物（目标 2），并检查自杀与自杀之间的关系 以及 BPD 相关的行为内表型和 mGluR5 可用性（目标 3）。这项研究的结果将提供 对这一新分子靶点与 BPD 症状学之间关系的潜在关键洞察。 完成拟议的培训计划和研究项目将使候选人处于最佳位置，以开发 作为一名分子成像研究员，能够为自杀预防工作做出有意义的贡献。