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: 9756464
• 负责人: Margaret Taylor Davis
• 金额: $ 19.64万
• 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/9756464
• 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; treatment risk

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.

这份有指导的临床科学家研究和职业发展建议旨在提供 应聘者具有高级培训、专家指导和实践研究经验，以促进 学术研究生涯。候选人的首要目标是成为一名独立的分子成像 研究高危人群自杀的神经生物学的研究人员。为了实现这一目标，我们提出了一种 全面的五年计划，旨在提供四个关键领域的严格培训：1)设计和实施 临床高危人群的PET研究；2)PET数据的获取和分析；以及3)高级统计学 分析；4)负责任的研究行为。这项提案将以多样化、尖端的方式完成 科学环境(耶鲁医学院)。我们还建议开展一项新的研究项目，使用 一种独特高危人群的分子成像技术：边缘性人格障碍(BPD)。 BPD是一种毁灭性的精神疾病，自杀企图的风险高得惊人(高达75%)和 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 报告说，最近三分之二以上的自杀企图发生在患有BPD的个人身上。不幸的是， 大多数可用的治疗方法不能解决整体BPD症状的严重程度或迅速 降低自杀风险。磁共振成像研究加深了我们对BPD的认识 病理生理学，涉及额叶(dlPFC，OFC，ACC)和边缘(杏仁核，脑岛)区域的网络 BPD症状表现。然而，对BPD的分子机制的研究 病理生理学和自杀行为是促进小说发展的关键下一步 在这一人群中进行治疗并促进风险预防。 新的证据表明代谢性谷氨酸5受体(MGluR5)与BPD和自杀有关 行为。MGluR5在情绪调节和痛觉中起关键作用，而情绪调节和痛觉都是BPD的中枢 病理和自杀风险相关。此外，与mGluR5相关的基因与自杀企图和 死亡率。我们在患有BPD(n=7)的患者中的激动人心的试验数据显示，额叶-边缘mGluR5的利用率更高 大脑区域与BPD的病理生理学有关，在那些试图自杀的人中有很大的差异 过去的事。因此，我们建议通过研究mGluR5在体内的可用性来证实和扩大初步发现 在使用PET和高选择性放射性配体[18F]FPEB的BPD中(目标1)，评估 MGluR5作为BPD自杀未遂的生物标志物(目标2)，并检查自杀之间的关系 以及BPD相关的行为内表型和mGluR5的可用性(目标3)。这项研究的结果将提供 对这一新的分子靶点与BPD症状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应聘者处于最佳位置，以制定 作为一名分子成像研究人员，能够对自杀预防工作做出有意义的贡献。