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

本建议书是BLR&D TBI(CTBI)建议书(RFP#BX-19-006)合作建议书的一部分。 涉及三个独立但综合的提案，共同调查TBI 增强退伍军人的冲动和自杀行为。协作项目的基本原理是 将人体生物标记物分析与人体成像研究以及神经生物学机制相结合 在动物身上进行研究，了解脑外伤影响冲动和自杀行为的方式。 防止自杀是退伍军人管理局的主要优先事项。最重要的假设是，脑外伤增强了冲动，一种 自杀的危险因素，特别是在应对压力时，通过炎症和5-羟色胺功能障碍 系统和额叶电路。 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 更全面的理解，我们建议将人体研究与TBI结合起来 以血液生物标记物为桥梁，与脑外伤动物模型研究的自杀性相关。这将会实现的 通过以下目标：目标1是人类生物标记物研究。目标1.1。将专注于州方面，通过开展 印第安纳波利斯采集的血液样本的转录分析。我们将分为两组：自杀性脑损伤 其中70例为自杀性脑损伤，70例为无脑外伤后自杀。我们不会进行成像研究，而是使用 纵向设计，在急性住院精神病患者住院期间首先测试受试者的自杀倾向 (严重的构思、计划、尝试)，然后在3-6个月后在低自杀状态下进行随访。我们 假设炎症和5-羟色胺相关的转录物在急性住院患者和 非急性随访测试，但与没有脑外伤的自杀相比，有脑损伤的自杀患者的情况较少。目标1.2。将要 专注于性状方面，通过对来自布朗克斯VA(JJPVA)(n=140)的样本进行转录分析。 我们假设，与炎症和5-羟色胺相关的转录在脑外伤的自杀性中增加最多。 与无脑损伤的自杀相比，无自杀的脑损伤和非脑损伤的非自杀。目标2是动物模型 脑和血液生物标记物的融合研究。我们将对大脑和血液进行转录分析 来自新泽西退伍军人管理局(VANJHCS)的动物模型研究(n=160)的样本，更多的是实验 研究脑损伤和冲动的简单方法。我们假设我们将识别出共同的生物标记物 脑部和血液发生了方向性变化。目标3是人类和动物模型的翻译趋同 生物标记物数据，使用融合功能基因组分析。我们假设候选州和 在人类研究中跟踪与脑外伤(脑外伤-S)相关的自杀(意念、企图)的特征生物标记物将交叉- 与动物模型研究中的脑-血生物标记物进行验证。我们还将测试假设驱动的 一系列已知的与炎症(IL6，IFNG)，5-羟色胺(5HT2A，SLC6A4)和脑外伤(UCH-L1， GFAP-FDA于2018年批准)。探索性目标4将重点放在生物标记物和物候学的融合上 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记物与不同的 同一个人和不同人的行为方面，从而更好地理解 脑外伤、冲动和自杀之间的病理生理联系。我们将使用PhenoChipping方法 (尼库列斯库等人)2006)6，对表型组学和基因组学数据进行了分类。 美国军队的新创伤性脑损伤(TBI)病例数量在2006年翻了一番多 过去五年，并将继续增长。脑外伤是自杀的危险因素。此外，增加的冲动是 脑损伤后最常见的症状之一，本身就是自杀、抑郁和吸毒的危险因素 虐待。因此，找到增加自杀风险的客观生物标志物，并了解 导致脑外伤后高冲动的机制是切断脑外伤和脑损伤之间联系的关键 自杀。

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.