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: 9977813
• 负责人: Margaret Taylor Davis
• 金额: $ 19.69万
• 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/9977813
• 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.

这个指导临床科学家的研究和职业发展的建议，旨在提供