Testosterone and APOE genotype interactions following mild traumatic brain injury

轻度创伤性脑损伤后睾酮和 APOE 基因型相互作用

• 批准号: 9291741
• 负责人: Rebecca C. Klein
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291741
• 关键词: Acceleration; Adult; Affect; Affective; Afghanistan; Aging-Related Process; Alleles; Alzheimer' s Disease; Animal Model; Anxiety; Apolipoprotein E; Attenuated; Award; Behavioral; Brain; Brain Injuries; Chronic; Cognition Disorders; Cognitive; Cognitive deficits; Conflict (Psychology); Data; Deceleration; Doctor of Philosophy; Electrophysiology (science); Endocrine; Functional disorder; Funding; Genetic Risk; Genotype; Goals; Head; High Prevalence; Hormonal; Hormones; Human; Human Genetics; Hypogonadism; Impaired cognition; Individual; Inflammatory; Injury; Iraq; Knowledge; Learning; Long-Term Effects; Measures; Mediating; Mental Depression; Mental disorders; Meta-Analysis; Military Personnel; Modeling; Multiple Trauma; Mus; Nervous System Trauma; Outcome; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Physiological; Post-Traumatic Stress Disorders; Proteins; Reporting; Risk; Risk Factors; Structure; Survivors; Symptoms; Synapses; Testing; Testosterone; Therapeutic; Therapeutic Effect; Time; Traumatic Brain Injury; Unconscious State; Vertebral column; Veterans; adverse outcome; base; behavioral outcome; clinically relevant; cognitive function; cytokine; density; dentate gyrus; effective therapy; experience; genetic profiling; genetic risk factor; improved; improved outcome; injured; mild traumatic brain injury; motor deficit; mouse model; neural circuit; neurophysiology; personalized medicine; promoter; protein biomarkers; response; risk minimization; service member; spatial memory

Nearly 20% of US troops deployed in Iraq and Afghanistan conflicts are estimated to have suffered probable traumatic brain injury (TBI). Among survivors, the loss of circulating levels of testosterone (hypogonadism) is one of the most frequently reported deficits, and the long-term effects may dramatically increase the risk of multiple symptoms including PTSD, depression, anxiety, and cognitive loss. The 4 allele of apolipoprotein E is the strongest risk factor for developing Alzheimer’s disease and is also associated with a more severe outcome following TBI. Importantly, individuals who carry APOE4 are 10X more likely to develop AD compared to those without the allele. Given that both TBI and testosterone loss adversely impact neurophysiology, the purpose of this study is to test the hypothesis that APOE genotype and testosterone interact to increase the risk of brain injury and that hormone replacement may significantly improve outcome. We have developed a closed-head model of mild traumatic brain injury that simulates acceleration-deceleration of the head during a collision and produces immediate loss of consciousness, temporary motor deficits, and deficits in both spatial and non- spatial learning that persist for at least 1-3 months following injury. These cognitive deficits are genotype and testosterone level dependent at this time point. For this study, we will use human APOE targeted replacement mice, a mouse model that expresses human apoE proteins under endogenous control of the mouse promoter, to assess the effects of APOE genotype in the presence and absence of testosterone loss on outcomes following mild repetitive traumatic brain injury. Specifically, following repeated mild TBI, we will examine the relationship of APOE genotype and testosterone loss on 1) cognitive and behavioral function, as well as 2) synaptic structure and function. Finally we will investigate whether testosterone mediates brain function via inflammatory pathways in an APOE-dependent manner following TBI. Outcomes will be measured 3 and 15 months post-injury in sham and post-TBI gonadectomized mice in order to examine chronic effects during adulthood and the aging process. We will also assess the effects of hormone replacement on behavioral and physiological outcomes. As there are currently no effective treatments that improve outcome following TBI, hormone replacement may provide a potential therapeutic option to attenuate the onset of mental and cognitive disorders that result from hypogonadism, especially in veterans who are genetically at risk. By studying TBI, testosterone, and APOE in conjunction, we can investigate the possibility of personalizing treatments to patients based on their genetic profile, with the goal of minimizing risks and maximizing benefits.

据估计，部署在伊拉克和阿富汗冲突中的美军中有近 20% 幸存者中可能遭受了创伤性脑损伤（TBI）。 睾酮水平（性腺功能减退症）是最常报告的缺陷之一， 长期影响可能会大大增加多种症状的风险，包括创伤后应激障碍（PTSD）、 载脂蛋白 E 的 4 等位基因是最大的风险。 是导致阿尔茨海默病的一个因素，也与更严重的后果有关 重要的是，携带 APOE4 的人患 AD 的可能性增加 10 倍。 与那些没有等位基因的人相比，TBI 和睾酮水平都会下降。 影响神经生理学，本研究的目的是检验 APOE 基因型的假设 和睾酮相互作用会增加脑损伤的风险，而激素替代可能会增加 我们已经显着开发了轻度创伤性脑部的闭头模型。 模拟碰撞过程中头部加速-减速并产生的伤害 意识立即丧失、暂时性运动缺陷以及空间和非运动能力缺陷 受伤后持续至少 1-3 个月的空间学习能力是指认知缺陷。 在本研究中，我们将使用人类。 APOE靶向替代小鼠，一种在蛋白质下表达人类apoE的小鼠模型 小鼠启动子的内源控制，以评估 APOE 基因型在 轻度重复性创伤后睾酮丢失的存在与否对结局的影响 具体来说，在反复轻度 TBI 后，我们将检查 APOE 的关系。 基因型和睾酮损失影响 1) 认知和行为功能，以及 2) 突触 最后我们将研究睾酮是否介导大脑功能。 TBI 后以 APOE 依赖性方式通过炎症途径进行治疗。 在假手术和 TBI 后去性腺切除的小鼠中，在受伤后 3 个月和 15 个月进行了测量，以便 检查成年期和衰老过程中的慢性影响我们还将评估其影响。 激素替代对行为和生理结果的影响目前还没有。 改善 TBI 后预后的有效治疗方法，激素替代疗法可能会提供 减轻由此导致的精神和认知障碍发作的潜在治疗选择 性腺功能减退症，尤其是有遗传风险的退伍军人。 睾酮和 APOE 结合起来，我们可以研究个性化的可能性 根据患者的基因图谱进行治疗，目的是最大限度地降低风险和 利益最大化。