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.

这项修订的临床科学家研究和职业发展计划旨在提供 候选人高级培训，专家心理和动手研究经验，以促进发展 学术研究职业。候选人的主要目标是成为独立的分子成像 研究人员研究高危人群中自杀的神经生物学。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）设计和行为 高危临床人群的宠物研究； 2）宠物数据获取和分析； 3）高级统计 分析; 4）负责任的研究。该建议将在潜水员的尖端完成 科学环境（耶鲁大学医学院）。我们进一步提出了使用新颖的研究项目的行为 独特的高危人群中的分子成像技术：边缘性人格障碍（BPD）。 BPD是一种毁灭性的精神病，自杀企图的风险令人震惊（最高75％）和 死亡率（最高10％）。尽管BPD的患病率相对较低（1-3％），但最近两项流行病学研究 报道说，BPD患者发生了最近三分之二的自杀企图。很遗憾， 大多数可用治疗方法无法解决总体BPD症状严重程度或迅速解决 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，暗示额叶（DLPFC，OFC，ACC）和边缘（杏仁核）区域的网络 BPD符号演示。然而，研究分子机制扩散BPD 病理生理学和自杀行为是促进新颖发展的重要下一步 该人群中的治疗和紧急风险预防。 新兴证据意味着BPD和自杀中的代谢型谷氨酸5受体（MGLUR5） 行为。 mglur5在情绪调节和疼痛感中扮演着关键的作用，这都是BPD的核心 病理学，与自杀风险有关。此外，与MGLUR5相关的基因与自杀企图有关 死亡。我们在BPD患者（n = 7）中令人兴奋的飞行员数据显示了额fllimvic中较高的MGLUR5可用性 大脑区域将BPD病理生理学联系在一起，在试图自杀的人中差异很大 过去。因此，我们建议通过研究MGLUR5在体内的可用性来确认和扩展初始发现 在BPD中，使用PET和高度选择性的放射线[18F] FPEB（AIM 1），评估了潜在的作用 MGlur5作为BPD自杀尝试的生物标志物（AIM 2），并检查自杀之间的关系 和与BPD相关的行为内表型和MGLUR5的可用性（AIM 3）。这项研究的结果将提供 对这个新型分子靶标与BPD症状之间的关系的潜在批判性洞察力。 拟议的培训计划和研究项目的完成将最佳地定位候选人，以开发一个 作为分子成像研究人员的职业，能够有意义地促进预防自杀的工作。