GLUT 1 Polymorphism Decreases Incidence of Depression and PTSD after Trauma

GLUT 1 多态性降低创伤后抑郁和 PTSD 的发生率

• 批准号: 8785491
• 负责人: Gretchen N Neigh
• 金额: $ 7.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785491
• 关键词: Address; Alzheimer' s Disease; Animal Model; Animals; Area; Astrocytes; Award; Behavior; Behavior Disorders; Behavioral; Behavioral Research; Behavioral Sciences; Blood - brain barrier anatomy; Brain; Cerebrum; Clinical; DNA; Data; Data Analyses; Data Set; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Economic Burden; Endothelial Cells; Energy Supply; Environment; Environmental Exposure; Evaluation; Event; Family; Foundations; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Glucose; Glucose Transporter; Glutamates; Goals; Human; Image; Impairment; Incidence; Individual; Investigation; K-18 conjugate; Knowledge; Lead; Link; Major Depressive Disorder; Malignant Neoplasms; Mediating; Mental Depression; Mental Health; Mental disorders; Mentors; Metabolic; Metabolism; Movement; Multivariate Analysis; Neurobiology; Neurons; Outcome; Participant; Pathology; Patients; Physiological; Post-Traumatic Stress Disorders; Promoter Regions; Proteins; Quality of life; Recording of previous events; Relative Risks; Research; Research Personnel; Resistance; Risk; Rodent Model; Role; SLC2A1 gene; Sampling; Scientist; Secure; Single Nucleotide Polymorphism; Stress; Testing; Time; Tissues; Training; Trauma; Traumatic Brain Injury; United States; United States National Institutes of Health; Urban Population; Variant; Work; base; behavioral/social science; career; disability; experience; glucose transport; glucose uptake; high risk; improved; innovation; insight; member; neuropsychiatry; novel; novel therapeutics; outcome forecast; programs; public health relevance; relating to nervous system; resilience; sample collection; skills; tumor progression

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.

基本行为和社会科学的短期指导职业提升奖：动物模型和人类调查（K18）交叉点的交叉培训是一个独特的机会，可以资助重大和创新的研究，同时建立技能集，从而提高科学家未来的科学发现潜力。目前的申请建议为Gretchen Neigh博士提供人体调查方面的培训，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。Neigh博士的研究集中在行为障碍的潜在代谢基础上，如重度抑郁症（MDD）和创伤后应激障碍（PTSD）。这项工作的双重目的是将Neigh博士关于葡萄糖转运和神经精神疾病起源的创新假设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。这种培训经验将为Neigh博士的研究计划中的翻译互惠性提供基础，并解决一个具有根本重要性的问题：评估代谢在MDD和/或PTSD表现中的潜在作用。在美国，超过2300万人患有MDD或PTSD，这些疾病损害生活质量并产生重大的经济负担。人类和动物研究都提供了这些条件和相关动物模型中脑代谢变化的证据。代谢活动的改变通常归因于神经元释放的谷氨酸减少，从而减少了局部葡萄糖转运。与这一传统教条相反， 在促进葡萄糖转运随后抑制神经元活动。促进葡萄糖转运由转运蛋白家族（GLUT）介导，所述转运蛋白家族负责葡萄糖转运穿过血脑屏障的内皮细胞，以及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学病症有关，包括阿尔茨海默病、缺血后脑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改变神经元能量供应，从而改变神经元功能，随后改变行为。GLUT 1的多态性已在人类中得到证实，并与癌症和糖尿病肾病的进展和预后改变有关。由于表达的遗传差异，GLUT 1的可用性的改变可能改变创伤后异常行为发展的相对风险，导致MDD和/或PTSD的表现。考虑到GLUT蛋白在能量底物转运到脑组织中的关键作用，神经精神疾病中脑代谢改变的证据，以及动物模型中应激暴露后葡萄糖转运蛋白改变的证据，拟议的工作测试了GLUT 1多态性将降低创伤暴露后MDD和/或PTSD发病率的假设。这项工作挑战了标准范式，因为脑GLUT是MDD和PTSD病理生理学考虑的新起点，因为人们普遍认为，患者成像中记录的葡萄糖转运变化是神经元活动改变的结果， 与神经元活动改变的原因相反。具体目标1将确定GLUT 1的多态性在多大程度上减少创伤暴露后MDD的表现。将评估DNA样本中GLUT 1的rs710218多态性。将进行多变量分析以确定暴露于创伤并具有多态性的个体是否对MDD的表现具有抗性。具体目标2将确定GLUT 1多态性降低创伤暴露后PTSD发病率的程度。与目标1中描述的工作类似，目标2将再次评估GLUT 1多态性对创伤结局的影响，但在这种情况下，重点将放在PTSD上。完成拟议的工作将提供新的和创新的洞察力，潜在的代谢易感性的遗传起源创伤引起的心理健康损害。对代谢因素在行为障碍表现中的作用的认识将为新的治疗选择提供一个新的考虑方向。此外，拟议的工作将促进交叉培训的一个既定的行为神经科学家，博士格雷琴尼，目前专门从事调查的神经基板的行为使用动物模型，在人类的调查。Neigh博士的培训将导致她的研究计划中的翻译互惠性增加，并通过她与学员和合作者的互动将改善行为科学中临床和基础研究人员之间的互动。