CTBI: Traumatic brain injury-induced inflammation effects on cognitive evaluations and response inhibition: Mechanisms of increased risk for suicidality

CTBI：创伤性脑损伤诱发的炎症对认知评估和反应抑制的影响：自杀风险增加的机制

• 批准号: 9891813
• 负责人: Alexander B Niculescu
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891813
• 关键词: Acute; Animal Model; Animals; Area; Award; Behavioral; Biological Markers; Blood; Blood specimen; Brain; Clinical; Cognitive; Data; Diagnosis; Diagnostic; Disease; Drug abuse; Enrollment; Evaluation; FDA approved; Foundations; Functional disorder; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Hospitalization; Human; IL6 gene; Image; Impulsive Behavior; Impulsivity; Individual; Inflammation; Inflammatory; Inpatients; Interferon Type II; Link; Mental Depression; Military Personnel; Molecular; Neurobiology; Neurons; New Jersey; Patient Self-Report; Patients; Peripheral; Prevention; Rattus; Recording of previous events; Research; Risk; Risk Factors; Sampling; Series; Serotonergic System; Serotonin; Site; Stress; Study Subject; Study models; Suicide; Suicide attempt; Suicide prevention; Symptoms; Testing; Transcript; Traumatic Brain Injury; Veterans; Visit; clinical application; clinically relevant; experimental study; follow-up; frontal lobe; functional genomics; genomic data; high risk; human imaging; human model; human subject; ideation; imaging study; longitudinal design; neural circuit; neurobehavioral test; neuroinflammation; phenomics; response; secondary analysis; suicidal; suicidal behavior; suicidal risk; trait; transcriptomics

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine human biomarker analysis, with human imaging studies, and with neurobiological mechanistic studies in animals, to understand the manner in which TBI influences impulsivity and suicidal behavior. Preventing suicide is a major priority for the VA. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide, particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. At the Indianapolis VA (INDVA) site, in order first to test our overarching hypothesis, and second to gain a more comprehensive understanding, we propose to translationally integrate human studies of subjects with TBI and suicidality with animal model studies of TBI, using blood biomarkers as a bridge. This will be accomplished via the following Aims: Aim 1 is Human biomarker studies. Aim 1.1. will focus on state aspects, by conducting transcriptomic analyses on blood samples collected in Indianapolis. We will have two groups: suicidality with TBI (n= 70) and suicidality without TBI (n= 70). We will not be conducting imaging studies, but rather use a longitudinal design, by testing the subjects first during an acute inpatient psychiatric hospitalization for suicidality (severe ideation, plan, attempt), and then 3-6 months later for a follow-up visit in a low suicidality state. We hypothesize that inflammatory and serotonin related transcripts will be decrease between acute inpatient and non-acute follow-up testing, but less so in suicidality with TBI compared to suicidality without TBI. Aim 1.2. will focus on trait aspects, by conducting transcriptomic analyses on samples from the Bronx VA (JJPVA) (n=140). We hypothesize that inflammatory and serotonin related transcripts will be increased most in suicidality with TBI compared to suicidality without TBI, TBI without suicidality, and non-TBI, non- suicidality. Aim 2 is Animal model brain and blood biomarkers convergence studies. We will conduct transcriptomic analyses of brain and blood samples from the animal model studies (n= 160) at the New Jersey VA (VANJHCS), a more experimentally tractable way of studying TBI and impulsivity. We hypothesize that we will identify biomarkers that are co- directionally changed in brain and blood. Aim 3 is Translational convergence of human and animal model biomarker data, using Convergent Functional Genomics analyses. We hypothesize that the candidate state and trait biomarkers that track suicidality (ideation, attempts) related to TBI (TBI-S) in the human studies will cross- validate with the brain-blood biomarkers from the animal model studies. We will also test hypothesis driven a series of known biomarkers related to inflammation (IL6, IFNG), serotonin (5HT2A, SLC6A4), and TBI (UCH-L1, GFAP- FDA approved in 2018). Exploratory Aim 4 will focus on convergence of biomarkers and phenomic data (neurobehavioral testing, imaging). We hypothesize that we can link different biomarkers to different behavioral aspects in the same individual and across individuals, resulting in a better understanding of the pathophysiological links between TBI, impulsivity, and suicidality. We will use a PhenoChipping approach (Niculescu et al. 2006)6, that clusters phenomics and genomics data. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, finding objective biomarkers of increased risk of suicide and understanding the mechanisms responsible for high impulsivity following TBI are key to severing the link between TBI and suicide.

本优秀提案是BLR&D合作优秀奖TBI（CTBI）提案（RFP #BX-19-006）的一部分 涉及三个独立但综合的建议，共同研究TBI的机制， 增强了退伍军人的冲动和自杀行为。合作项目的基本原理是 联合收割机将人类生物标志物分析与人类成像研究和神经生物学机制结合起来， 动物研究，以了解TBI影响冲动和自杀行为的方式。 预防自杀是退伍军人事务部的首要任务。最重要的假设是，TBI增强了冲动性， 自杀的危险因素，特别是对压力的反应，通过炎症和5-羟色胺功能障碍 系统和额叶回路。 在印第安纳波利斯VA（INDVA）现场，为了首先测试我们的总体假设，其次获得一个 更全面的理解，我们建议将TBI受试者的人类研究与TBI结合起来， 和自杀倾向与TBI动物模型研究，使用血液生物标志物作为桥梁。这将是完成 通过以下目的：目的1是人类生物标志物研究。目标1.1。将重点放在国家方面，通过开展 在印第安纳波利斯收集的血液样本的转录组学分析。我们将分为两组：TBI自杀 （n= 70）和自杀无TBI（n= 70）。我们不会进行成像研究，而是使用 纵向设计，首先在急性住院精神病患者住院期间测试受试者的自杀倾向 （严重意念、计划、企图），然后在3-6个月后以低自杀倾向状态进行随访。我们 假设炎症和5-羟色胺相关转录物在急性住院患者和 非急性随访测试，但与无TBI的自杀相比，TBI的自杀率较低。目标1.2。将 通过对来自布朗克斯VA（JJPVA）（n=140）的样品进行转录组学分析，专注于性状方面。 我们推测，炎症和5-羟色胺相关的转录将增加最自杀与创伤性脑损伤 与无TBI的自杀倾向，无自杀倾向的TBI，以及非TBI，非自杀倾向相比。目标2：动物模型 大脑和血液生物标志物的融合研究。我们将对大脑和血液进行转录组学分析 来自新泽西VA（VANJHCS）动物模型研究的样本（n= 160）， 研究创伤性脑损伤和冲动性的好方法我们假设，我们将确定共同的生物标志物， 在大脑和血液中发生方向性改变。目标3是人类和动物模型的平移收敛 生物标志物数据，使用Convergent Functional Genomics分析。我们假设候选国和 在人类研究中追踪与TBI（TBI-S）相关的自杀倾向（意念，企图）的性状生物标志物将交叉- 用动物模型研究的脑血生物标志物进行验证。我们还将测试假设驱动a 一系列已知的与炎症相关的生物标志物（IL 6，IFNG），血清素（5 HT 2A，SLC 6A 4），和TBI（UCH-L1， GFAP- FDA于2018年批准）。探索性目标4将侧重于生物标志物和表型的融合 数据（神经行为测试，成像）。我们假设我们可以将不同的生物标志物与不同的 行为方面在同一个人和跨个人，从而更好地了解 创伤性脑损伤、冲动性和自杀倾向之间的病理生理学联系。我们将使用PhenoChipping方法 （Niculescu等人，2006年）6，聚类表型组学和基因组学数据。 美国军队的新创伤性脑损伤（TBI）病例数量在2010年增加了一倍多。 五年，并将继续增长。TBI是自杀的危险因素。此外，增加的冲动是 这是TBI后最常见的症状之一，本身也是自杀，抑郁和药物的风险因素 虐待因此，找到自杀风险增加的客观生物标志物并了解自杀风险， 负责TBI后高冲动性的机制是切断TBI和TBI之间联系的关键。 自杀