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

这个指导临床科学家的研究和职业发展建议的目的是提供 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独立的分子成像 研究高危人群自杀的神经生物学的研究员。为了实现这一目标，我们提出了一个 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 高风险临床人群中的PET研究; 2）PET数据采集和分析;以及3）高级统计 （4）分析;（5）研究。这一建议将在一个多样化的，前沿完成 科学环境（耶鲁医学院）。我们还建议进行一项新的研究项目， 分子成像技术在一个独特的高危人群：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%）， 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，最近超过三分之二的自杀企图发生在BPD患者中。不幸的是， 大多数可用的治疗方法不能解决BPD症状的整体严重程度或快速 降低自杀风险。磁共振成像研究增强了我们对BPD的认识 病理生理学，涉及额叶（dlPFC，OFC，ACC）和边缘（杏仁核，杏仁核）区域的网络， BPD症状表现。然而，研究BPD的分子机制 病理生理学和自杀行为是一个必不可少的下一步，既促进发展的小说 治疗，并促进这一人群的风险预防。 新出现的证据表明代谢型谷氨酸5受体（mGluR 5）在BPD和自杀性 行为mGlur 5在BPD的情绪调节和疼痛感知中起着关键作用，这两者都是BPD的核心 病理学和自杀风险有关。此外，与mGluR 5相关的基因与自杀企图有关， mortality.我们在患有BPD的个体（n=7）中的令人兴奋的试验数据显示，在额叶-顶叶中mGluR 5的可用性更高。 大脑区域与BPD病理生理学相关，在那些试图自杀的人中， 过去因此，我们建议通过研究体内mGluR 5的可用性来证实和扩展初步的研究结果 在BPD中使用PET和高选择性放射性配体[18F]FPEB（目的1），评估 mGluR 5作为BPD中自杀企图的生物标志物（目的2），并检查自杀与 和BPD相关的行为内表型和mGluR 5可用性（目的3）。这项研究的结果将提供 潜在的关键洞察之间的关系，这种新的分子靶点和BPD的药理学。 完成拟议的培训计划和研究项目将使候选人处于最佳地位， 作为一名分子成像研究人员，能够为预防自杀做出有意义的贡献。

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.