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: 10222613
• 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 2021-11-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222613
• 关键词: Acceleration; Adult; Affect; Affective; Afghanistan; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; 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; 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; Process; 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 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.

估计在伊拉克和阿富汗冲突中部署的美军中有近20％估计 脑损伤有问题（TBI）。在生存中，循环丧失 睾丸激素水平（性腺功能减退）是最常见的缺陷之一，并且是 长期影响可能会大大增加多种症状的风险，包括PTSD， 抑郁，焦虑和认知丧失。 apolipoprotion E的4等位基因是强烈的风险 发展阿尔茨海默氏病的因素，也与更严重的结果有关 遵循TBI。重要的是，携带APOE4的个人开发广告的可能性更高 与没有等位基因的人相比。鉴于TBI和睾丸激素损失都不利 影响神经生理学，这项研究的目的是检验APOE基因型的假设 睾丸激素相互作用以增加脑损伤的风险，而替代马龙可能 显着改善结果。我们已经开发了一种轻度创伤性大脑的闭合头模型 在碰撞期间模拟头部加速度的伤害并产生 直接丧失意识，暂时的运动缺陷以及空间和非 - 受伤后至少1-3个月持续存在的空间学习。这些认知定义是 基因型和睾丸激素水平依赖于此时间点。对于这项研究，我们将使用人类 APOE靶向替换小鼠，一种在下面表达人apoE蛋白的小鼠模型 对小鼠启动子的内源性控制，以评估APOE基因型在 轻度重复创伤后，在结局上的存在和不存在 脑损伤。具体而言，在重复轻度TBI之后，我们将检查APOE的关系 1）认知和行为功能的基因型和睾丸激素丧失，以及2）突触 结构和功能。最后，我们将研究睾丸激素是否介导大脑功能 通过TBI之后以APOE依赖性方式通过炎症途径。结果将是 在假手术后和TBI后促性切除术后3个月和15个月测量，以便为了 检查成年期间的慢性影响和衰老过程。我们还将评估效果 在行为和身体结果上替代激素。因为目前没有 有效的治疗方法可以改善TBI后的结果，Horseone替换可能会提供 潜在的治疗选择，以减弱导致心理和认知障碍的发作 来自遗传上有风险的退伍军人，尤其是在疾病中。通过研究TBI， 睾丸激素和APOE结合使用，我们可以调查个性化的可能性 根据患者的遗传特征对患者进行治疗，目的是最大程度地降低风险和 最大化收益。

项目成果

Effects of sex and genotype in human APOE-targeted replacement mice on alcohol self-administration measured with the automated IntelliCage system before and after repeated mild traumatic brain injury.

• DOI: 10.1111/acer.14717
• 发表时间: 2021-11
• 期刊: Alcoholism, clinical and experimental research
• 作者: Simmons KE;Healey KL;Li Q;Moore SD;Klein RC
• 通讯作者: Klein RC

Multiple sources of internal calcium stores mediate ethanol-induced presynaptic inhibitory GABA release in the central nucleus of the amygdala in mice.

• DOI: 10.1007/s00213-020-05613-w
• 发表时间: 2020-11
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Li Q;Klein RC;Moore SD
• 通讯作者: Moore SD