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: 10417014
• 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/10417014
• 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.

该优点提案是TBI（CTBI）提案（RFP＃BX-19-006）的BLR＆D协作功绩奖的一部分 涉及三个独立但集成的建议，共同研究了TBI的机制 增强了退伍军人的冲动性和自杀行为。协作项目的理由是 将人类生物标志物分析与人类成像研究和神经生物学机械结合在一起 在动物中的研究，以了解TBI影响冲动和自杀行为的方式。 预防自杀是VA的主要优先事项。总体假设是TBI增强了冲动性，一个 自杀的危险因素，尤其是通过炎症和功能障碍的响应压力的危险因素 系统和额叶电路。 在印第安纳波利斯VA（INDVA）地点，首先要检验我们的总体假设，其次是获得 我们提出了更全面的理解，建议将人类对受试者的研究与TBI的研究整合 对TBI动物模型研究的自杀性，使用血液生物标志物作为桥梁。这将完成 通过以下目的：AIM 1是人类生物标志物研究。目标1.1。通过进行 对印第安纳波利斯收集的血液样本的转录组分析。我们将有两个小组：自杀性TBI （n = 70）和没有TBI的自杀性（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医院治疗自杀性期间对受试者进行测试 （严重的构想，计划，尝试），然后在3-6个月后以低自杀状态进行后续访问。我们 假设炎症性和5-羟色胺相关的转录本将减少急性住院和 非急性随访测试，但与没有TBI的自杀性相比，对TBI的自杀性较少。目标1.2。将要 专注于性状方面，通过对布朗克斯VA（JJPVA）样品进行转录组分析（n = 140）。 我们假设炎症性和5-羟色胺相关的成绩单将在自杀性中最大增加 与没有TBI的自杀性，无自杀性的TBI和非TBI，非自杀性。 AIM 2是动物模型 脑和血液生物标志物收敛研究。我们将进行大脑和血液的转录组分析 来自新泽西VA（Vanjhcs）的动物模型研究的样本（n = 160），这是一个更实验的 研究TBI和冲动的可探讨方式。我们假设我们将确定共同的生物标志物 大脑和血液方向改变。 AIM 3是人类和动物模型的转化融合 生物标志物数据，使用收敛功能基因组学分析。我们假设候选国家和 人类研究中与TBI（TBI-S）相关的自杀性（构想，尝试）的特质生物标志物将跨 用动物模型研究验证脑血生物标志物。我们还将检验假设驱动的 与炎症（IL6，IFNG），5-羟色胺（5HT2A，SLC6A4）和TBI有关的一系列已知生物标志物（IL6，IFNG）和TBI（UCH-L1， GFAP-FDA于2018年批准）。探索目标4将重点放在生物标志物和现象的收敛上 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生物标志物联系起来 同一个人和跨个体的行为方面，从而更好地理解 TBI，冲动性和自杀性之间的病理生理联系。我们将使用现象方法 （Niculescu等，2006）6，簇现象学和基因组学数据。 美国军事力量的新脑损伤（TBI）案件的数量增加了一倍以上 最近五年将继续增长。 TBI是自杀性的危险因素。而且，增加的冲动是 TBI后最普遍的症状之一，本身就是自杀，抑郁和毒品的危险因素 虐待。因此，发现自杀风险增加并理解的客观生物标志物 TBI后负责高冲动性的机制是切断TBI和TBI之间联系的关键 自杀。