Neuroinflammatory and Epigenetic Mechanisms of Blood-Brain Barrier Compromise in Suicide

自杀中血脑屏障受损的神经炎症和表观遗传机制

基本信息

批准号：
10554314
负责人：
FATEMEH G HAGHIGHI
金额：
--
依托单位：
JAMES J PETERS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554314
关键词：
Affect Age Anti-Inflammatory Agents Area Astrocytes Autopsy Behavioral Biochemical Biological Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood Vessels Blood specimen Brain Brain imaging CCL3 gene CD44 gene Cause of Death Cell Death Cerebral cortex Cerebrospinal Fluid Cessation of life Characteristics Clinical Collection Communicable Diseases Confounding Factors (Epidemiology)DNA Methylation Data Deposition Detection Development Diagnostic Disease Disease susceptibility Dorsal Epigenetic Process Event Exposure to Extravasation Feeling suicidal Fibrinogen Fibronectins Gene Expression Profiling Genes Genetic Polymorphism Genetic Transcription Goals Health Histologic Hospitalization Immune response Immune system Impairment Individual Infection Inflammation Inflammatory Intervention Investigation Knowledge Laboratories Laboratory Animals Leukocytes Life Stress Link Magnetic Resonance Imaging Matrix Metalloproteinases Measures Mental Depression Mental disorders Metalloproteases Methods Methylation Microglia Modeling Molecular Neuroanatomy Neurobiology Neurons Noise Non-Invasive Detection Nucleic Acid Regulatory Sequences Pattern Peripheral Persons Phagocytes Phenotype Plasma Proteins Predisposition Prefrontal Cortex Preventive treatment Probability Procedures Process Prospective Studies Proteins Proteomics Protocols documentation Recording of previous events Regulator Genes Reporting Research Risk Reduction Sampling Schizophrenia Serum Serum Proteins Services Signal Transduction Site Stress Suicide Suicide attempt Surface Surveys Testing Tight Junctions Time Tissue Sample Transcript Transcriptional Regulation Veterans age group blood-brain barrier crossing blood-brain barrier disruption blood-brain barrier function blood-brain barrier permeabilization cerebral microvasculature contrast enhanced cytokine design diagnostic tool epigenetic marker functional disability genome wide methylation genome-wide glial activation gray matter high risk in vivo methylation pattern military veteran molecular marker nervous system disorder neuroinflammation novel promoter psychologic research clinical testing response schizophrenia spectrum disorder secondary analysis serotonin transporter sex suicidal suicidal act suicidal behavior suicidal risk suicide attempter suicide victim targeted treatment transcriptomics white matter

项目摘要

We propose a set of studies focused on the association of suicide with neuroinflammation and compromise of the blood-brain barrier, with the goal of identifying a pattern of quantifiable abnormalities that could serve as a biomarker for imminent suicidal risk in our Veterans. Autopsy studies are uniquely suited to do this, because they capture the state of the brain at the time of the suicidal act. Findings from our laboratories and others indicate that susceptibility to suicide includes inflammatory activation in the brain and systemically, accompanied by compromised integrity of the blood-brain barrier: (1) Most directly, we reported increased densities of microglia or other phagocytic cells associated with blood vessels in dorsal prefrontal white matter of people who died by suicide, Similar results are reported in cingulate white matter. (2) Studies of brains from individuals who died by suicide and studies of blood and CSF from live individuals who had previously attempted suicide found elevations of inflammatory cytokines. (3) Various infectious diseases are associated with increased risk of suicide, as is a history of hospitalization for any infection. (4) Laboratory animals exposed to stress show elevated levels of inflammatory cytokines, increased permeability of the blood-brain barrier, behavioral abnormalities, and activation of microglia. (5) We have reported an association of suicide with a polymorphism and decreased frontal and cingulate transcripts for CD44, which is involved in the normal function of the BBB. (6) Biochemical measures suggesting BBB impairment are reportedly associated with attempted suicide and with suicidal ideation. (7) In MDD subjects who died by suicide, compared with nonpsychiatric non-suicide cases, we found differential methylation of genes associated with cell death, both in whole cortical homogenates and in purified neuronal fractions. We also found significantly lower methylation in the promoter of the gene for CCL3, a powerful inflammatory cytokine synthesized by microglia and astrocytes and an attractant for microglia and white blood cells, but this difference was not present in the purified neuronal fraction. Taken together, these findings lead us to hypothesize a suicidal state characterized by impaired BBB function, elevation of pro-inflammatory cytokines, and abnormalities in DNA methylation of genes stimulating inflammation, all of which can be assessed in live individuals. To confirm this phenotype, we propose three specific aims, each employing the same set of 90 autopsy brains, already collected. In order to distinguish features of suicide from those of psychiatric illness, we employ a 3-group design with 30 cases of psychiatric disease and suicide, 30 cases of psychiatric disease without suicide, and 30 cases with neither psychiatric disease nor suicide, all from a well-characterized collection with a single collection protocol at a single autopsy service. To optimize our ability to distinguish features of suicide from those of psychiatric disease, in addition to finding the best matches between groups by age and sex, we sought to limit all of the psychiatric cases to a single clinical group, which was best achieved with schizophrenia spectrum disorders. Our specific aims, for each of which we will assay cerebral cortex and white matter from dorsal and ventral prefrontal regions, are: (1) To evaluate functional BBB impairment by stereological assessment of perivascular deposits of fibronectin. (2) To quantify a panel of cytokines, and to look for structural evidence of BBB impairment by assaying isolated microvessel fractions for vascular tight junction proteins and matrix metalloproteases.(3) To identify transcriptional correlates of BBB alterations with a genome-wide methylation survey on microvessel fractions of cortex and white matter from each region, using the Illumina Infinium MethylationEPIC microarray .These data will allow us to establish the underlying abnormalities for development of a suicidal profile to better, identify and treat veterans at risk of suicide. Knowledge and application of this profile will save Veterans’ lives by identifying potential targets for novel clinical interventions.

我们提出了一组专注于自杀与神经炎症和血脑屏障的妥协，目的是确定一种可量化异常的模式可以作为我们退伍军人迫在眉睫的自杀风险的生物标志物。尸检研究非常适合这是因为他们在自杀行为时捕获了大脑的状态。我们实验室和其他实验室的发现表明，自杀的易感性包括炎症大脑中的激活和系统地激活，通过血脑屏障的完整性受损而实现：（1）我们最直接地报道了与血液相关的小胶质细胞或其他吞噬细胞的密度增加死于自杀的人的背额前白质船只，报道了类似的结果。白质。（2）对死于自杀的人的大脑以及对血液和CSF的研究以前曾尝试自杀的人发现炎症细胞因子的升高。（3）各种传染病与自杀风险增加有关，任何住院病史感染。（4）暴露于应力的实验动物显示炎症细胞因子水平升高，增加血脑屏障，行为异常和小胶质细胞激活的渗透性。（5）我们有报道了自杀与多态性的关联，并改善了额叶和扣带的转录本 CD44，参与BBB的正常功能。（6）生化措施提示BBB 据报道，损害与自杀未遂和自杀想法有关。（7）在MDD主题中与非精神病案件相比，他死于自杀，我们发现与细胞死亡相关的基因，包括整个皮质匀浆和纯化的神经元部分。我们还发现CCL3基因启动子的甲基化显着降低，这是一种强大的炎症由小胶质细胞和星形胶质细胞合成的细胞因子以及小胶质细胞和白细胞的吸引力，但这是纯化的神经元部分中不存在差异。综上功能，促炎细胞因子的升高以及刺激基因DNA甲基化异常炎症，所有这些都可以在现场个体中进行评估。为了确认这种表型，我们提出了三个具体目的，每种目标都采用相同的90个尸检大脑，已经收集了。为了区分自杀的特征来自精神病疾病，我们采用3组设计的3组设计。疾病和自杀，30例无自杀的精神病病例，30例都没有精神病学病例疾病或自杀，全部来自一个充分的收藏，并具有单个尸检的单个收集方案服务。为了优化我们将自杀的特征与精神病疾病的特征区分开的能力，此外通过年龄和性别找到群体之间的最佳匹配，我们感觉到将所有精神病病例限制在单个临床组，最好通过精神分裂症谱系障碍来实现。我们的具体目标我们每个人都会主张背侧和腹侧前额叶区域的大脑皮层和白质，是：（1）通过对纤连蛋白的血管周期沉积物的立体评估来评估功能性BBB损伤。（2）量化一组细胞因子，并通过测定分离的BBB损害的结构证据血管紧密连接蛋白和基质金属蛋白酶的微血管级分。（3）识别 BBB改变的转录相关性与整个基因组甲基化调查有关微血管级的甲基化调查使用Illumina Infinium甲基化的微阵列，每个区域的皮质和白质。将使我们能够建立基本异常，以开发自杀状况，以更好，识别和治疗有自杀风险的退伍军人。此个人资料的知识和应用将通过识别来挽救退伍军人的生命新型临床干预措施的潜在目标。