APOE genotype effects on brain function following traumatic brain injury (TBI)

APOE 基因型对创伤性脑损伤 (TBI) 后脑功能的影响

• 批准号: 8821782
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821782
• 关键词: Afghanistan; Age-Months; Alleles; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Anxiety; Apolipoprotein E; Attenuated; Behavioral; Body Weight; Brain; Brain Injuries; Brain region; Closed head injuries; Cognition Disorders; Cognitive; Conflict (Psychology); Data; Disease; Emotional; Experimental Designs; Future; Genotype; Glucose; High Prevalence; Hippocampus (Brain); Hormones; Human; Human Genetics; Hypogonadism; Impaired cognition; Implant; Individual; Injury; Iraq; Long-Term Effects; Measures; Mental Depression; Mental disorders; Methods; Mission; Modeling; Motor; Mus; Neurological outcome; Neurons; Operative Surgical Procedures; Outcome; Outcome Measure; Pathway interactions; Pituitary Diseases; Pituitary Hormones; Plasma; Population; Post-Traumatic Stress Disorders; Proteins; Pump; Rehabilitation Research; Reporting; Research; Risk; Risk Factors; Services; Soldier; Structure; Survivors; Symptoms; Synapses; TBI Patients; Testing; Testosterone; Therapeutic; Time; Translational Research; Traumatic Brain Injury; Veterans; apolipoprotein E-3; apolipoprotein E-4; behavioral outcome; design; effective therapy; genetic risk factor; improved; meetings; member; mouse model; neurophysiology; prevent; public health relevance; research and development; synaptic function

DESCRIPTION (provided by applicant): It is estimated that nearly 20% of US troops deployed in Iraq and Afghanistan conflicts 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 of dramatically increase the risk of multiple symptoms including PTSD, depression, anxiety and cognitive loss. The e4 allele of apolipoprotein E is the strongest risk factor for developing Alzheimer's disease and is also associated with a worsened 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. Using a mouse model that expresses human apoE proteins, we will use a closed head injury model to assess the effects of testosterone loss and TBI on behavioral outcomes and neuronal structure and function (Aim 1). We will next assess the effects of hormone replacement on these outcomes (Aim 2). 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.

描述（由申请人提供）： 据估计，部署在伊拉克和阿富汗冲突中的美军中有近 20% 可能遭受过创伤性脑损伤 (TBI)。在幸存者中，睾酮循环水平的丧失（性腺功能减退症）是最常报告的缺陷之一，其长期影响是显着增加多种症状的风险，包括创伤后应激障碍（PTSD）、抑郁、焦虑和认知丧失。载脂蛋白 E 的 e4 等位基因是发生阿尔茨海默病的最强危险因素，也与 TBI 后的恶化结果相关。重要的是，携带 APOE4 的人患 AD 的可能性是没有等位基因的人的 10 倍。鉴于 TBI 和睾酮缺失都会对神经生理学产生不利影响，本研究的目的是检验 APOE 基因型和睾酮相互作用会增加脑损伤风险以及激素替代可能显着改善预后的假设。使用表达人类 apoE 蛋白的小鼠模型，我们将使用闭合性头部损伤模型来评估睾酮丧失和 TBI 对行为结果以及神经元结构和功能的影响（目标 1）。接下来我们将评估激素替代疗法对这些结果的影响（目标 2）。由于目前没有有效的治疗方法可以改善 TBI 后的预后，激素替代疗法可能提供一种潜在的治疗选择，以减轻性腺功能减退症引起的精神和认知障碍的发作，特别是对于有遗传风险的退伍军人。