GLUT 1 Polymorphism Decreases Incidence of Depression and PTSD after Trauma

描述(由申请者提供)：基础行为和社会科学短期辅导式职业发展奖：动物模型和人类调查交叉培训(K18)是一个独特的机会，可以资助重大和创新的研究，同时培养科学家的技能集，从而培养未来的科学发现潜力。目前的申请建议为格雷琴·尼尔博士提供人类调查方面的培训，他是一名行为神经内分泌学家，目前擅长使用动物模型来解决行为的神经生物学基础问题。尼尔博士的研究重点是行为障碍的潜在代谢基础，如严重抑郁障碍(MDD)和创伤后应激障碍(PTSD)。这项拟议的工作具有双重目的，即将尼尔博士关于葡萄糖运输和神经精神疾病起源的创新假说从她目前在啮齿动物模型中的工作扩展到使用人类调查进行评估。这一培训经验将为Neigh博士的研究计划中的翻译互惠提供基础，并解决一个至关重要的问题：评估代谢在MDD和/或PTSD表现中的潜在作用。美国有2300多万人患有MDD或创伤后应激障碍，这些疾病损害了生活质量，并产生了巨大的经济负担。人类和动物研究都提供了在这些条件下和相关动物模型中大脑代谢变化的证据。代谢活性的改变通常归因于神经元谷氨酸释放的减少，从而减少了局部葡萄糖的运输。与这一传统教条背道而驰的是，主要的变化可能是 在促进葡萄糖转运之后，会抑制神经元的活动。促进葡萄糖转运是由一系列转运蛋白(GLUT)介导的，这些转运蛋白负责葡萄糖跨血脑屏障内皮细胞的转运，并负责将葡萄糖摄取到星形胶质细胞和神经元中。GLUT家族成员的表达和易位缺陷与神经病理状况有关，包括阿尔茨海默病、脑缺血后功能和创伤后脑损伤缺陷。GLUT家族成员在血脑屏障内皮细胞、星形胶质细胞或神经元中的表达或易位的改变，可以改变神经元的能量供应，从而改变神经元的功能，从而改变行为。GLUT1基因的多态性已在人类中被证实，并与癌症和糖尿病肾病的进展和预后改变有关。由于基因表达的差异，GLUT1可获得性的改变可能改变创伤后发生异常行为的相对风险，导致MDD和/或PTSD的表现。考虑到GLUT蛋白在能量底物向脑组织运输中的关键作用，有证据表明神经精神疾病中大脑代谢发生了变化，以及有证据表明在动物模型中应激暴露后葡萄糖转运蛋白发生了变化，拟议的工作检验了GLUT 1基因多态将降低创伤暴露后MDD和/或PTSD发生率的假设。这项工作对标准范式提出了挑战，因为在MDD和PTSD的病理生理学中，脑供过于求是一个新的起始点，因为人们普遍认为，患者成像中记录的葡萄糖运输的变化是神经元活动改变的结果，如 与神经元活动改变的原因相反。具体目标1将确定GLUT 1基因的多态性在多大程度上降低创伤暴露后MDD的表现。DNA样本将在GLUT 1中评估rs710218多态。将进行多变量分析，以确定受过创伤并具有该多态的个体是否对MDD的表现具有抵抗力。具体目标2将确定GLUT 1基因的多态性在多大程度上降低创伤暴露后创伤后应激障碍的发生率。与目标1中描述的工作类似，目标2将再次评估GluT 1基因多态对创伤结局的影响，但在这种情况下，重点将放在创伤后应激障碍上。这项拟议工作的完成将为研究遗传性精神健康损伤的潜在代谢易感性提供新的和创新的见解。认识代谢因素在行为障碍表现中的作用将为新的治疗方案提供一个新的考虑方向。此外，拟议的工作还将促进著名的行为神经学家格雷琴·尼尔博士在人类调查中的交叉培训，他目前专门研究使用动物模型调查行为的神经基础。Neigh博士培训的加强将增加她的研究项目中的翻译互惠，并通过她与受训者和合作者的互动将改善行为科学领域的临床和基础研究人员之间的互动。

DESCRIPTION (provided by applicant): The Short-term Mentored Career Enhancement Award in Basic Behavioral and Social Sciences: Cross-Training at the Intersection of Animal Models and Human Investigation (K18) is a unique opportunity to fund significant and innovative research while simultaneously building the skill set, and thereby future scientific discovery potential, of a scientist. The current application proposes to secure training in human investigation for Gretchen Neigh, Ph.D., a behavioral neuroendocrinologist currently adept at the use of animal models to address questions of the neurobiological basis of behavior. Dr. Neigh's research portfolio focuses on potential metabolic underpinnings of behavioral disorders such as Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). The work proposed serves the dual purpose of extending Dr. Neigh's innovative hypotheses regarding glucose transport and origin of neuropsychiatric disorders from her current work in rodent models to assessments using human investigation. This training experience will provide a foundation for translational reciprocity in Dr. Neigh's research program and address a question of fundamental importance: assessment of the potential role of metabolism in manifestation of MDD and/or PTSD. Over 23 million people in the United States suffer from MDD or PTSD and these disorders compromise quality of life and generate significant economic burden. Both human and animal studies have provided evidence of changes in cerebral metabolism in these conditions and related animal models. The alterations in metabolic activity are generally attributed to reduced glutamate release from neurons which thereby decreases regional glucose transport. Counter to this traditional dogma, it is possible that a primary change in facilitated glucose transport subsequently suppresses neuronal activity. Facilitated glucose transport is mediated by a family of transporters (GLUT) that are responsible for glucose transport across the endothelial cells of the blood brain barrier, and for uptake of glucose into astrocytes and neurons. Deficits in the expression and translocation of members of the GLUT family have been linked to neuropathological conditions including Alzheimer pathology, post-ischemic brain function, and post- traumatic brain injury deficits. Alterations in the expression o translocation of members of the GLUT family in either the endothelial cells of the blood brain barrier, astrocytes, or neurons, could alter neuronal energy supply and thereby neuronal function, subsequently altering behavior. A polymorphism in GLUT1 has been demonstrated in humans and linked to altered progression and prognosis in cancer and diabetic nephropathy. Alterations in the availability of GLUT1, due to genetic differences in expression, may alter the relative risk 0f development of aberrant behaviors following trauma, leading to the manifestation of MDD and/or PTSD. Given the crucial role of GLUT proteins in the transport of energy substrates into cerebral tissue, evidence of altered cerebral metabolism in neuropsychiatric disorders, and evidence that glucose transporters are altered after stress exposure in animal models, the proposed work tests the hypothesis that a polymorphism in GLUT 1 will decrease the incidence of MDD and/or PTSD following trauma exposure. This work challenges the standard paradigm because cerebral GLUT is a novel point of origin for consideration in the pathophysiology of MDD and PTSD as it is generally accepted that the changes in glucose transport that are documented in imaging of patients are the result of altered neuronal activity as opposed to the cause of altered neuronal activity. Specific Aim 1 will determine the extent to which a polymorphism in GLUT 1 decreases the manifestation of MDD following trauma exposure. DNA samples will be assessed for the rs710218 polymorphism in GLUT 1. Multivariate analyses will be conducted to determine if individuals that have been exposed to trauma and have the polymorphism are resistant to the manifestation of MDD. Specific Aim 2 will ascertain the degree to which a polymorphism in GLUT 1 decreases the incidence of PTSD following trauma exposure. Similar to work described in Aim 1, Aim 2 will again assess the influence of the GLUT 1 polymorphism on outcome from trauma, but in this case the focus will be on PTSD. Completion of the proposed work will provide novel and innovative insight into a potential metabolic susceptibility of genetic origin to trauma-induced mental health impairments. Appreciation for the role of metabolic factors in the manifestation of behavioral disorders will provide a new direction of consideration for novel therapeutic options. In addition, the proposed work will facilitate the cross- training of an established behavioral neuroscientist, Dr. Gretchen Neigh, currently specialized in investigation of the neural substrates of behavior using animal models, in human investigation. Enhancement of Dr. Neigh's training will lead to increased translational reciprocity in her research program and through her interactions with trainees and collaborators will improve interactions between clinical and basic researchers in the behavioral sciences.