Genetics of Glutamatergic Neurotransmission

描述(由申请人提供)：这是一份R21提案，重点关注与大脑谷氨酸代谢相关的遗传变异和神经成像措施。谷氨酸是一种重要的神经递质，谷氨酸系统的异常已被报道在包括精神分裂症和双相情感障碍在内的主要精神疾病中。事实上，几种修改谷氨酸能神经传递的候选药物正在开发中，作为这些疾病的治疗方法。这种方法前景看好，但我们对谷氨酸代谢的分子决定因素或体内大脑谷氨酸探针的了解还不够深入，这些因素可以支持药物开发工作。PI是NIMH的R01持有者，其研究重点是优化脑谷氨酸和谷氨酰胺定量的质子磁共振波谱(MRS)序列，并使用MRS来探索患者群体中的区域谷氨酸动态。他最近开始与公认的精神病学遗传学专家乔丹·斯莫勒博士合作。这种合作导致了最近发表的数据表明谷氨酰胺酶(将谷氨酰胺转化为谷氨酸的酶)基因GLS1的变异与使用MRS测量的大脑谷氨酰胺/谷氨酸比率之间的关系。因此，GLS1的遗传变异与GLS1控制的代谢物水平在体内的变化有关。有了一种经过验证的神经成像方法，使我们能够量化体内大脑谷氨酸的动态，我们现在可以在一个能量充足的健康对照样本中实验测试这一假设。在这项建议的具体目标1中，我们建议在健康对照组的样本中检查GLS1基因变异与脑局部谷氨酰胺/谷氨酸比率之间的关系。在具体目标2中，我们将通过测试GLS1基因变异是否与N-乙酰天冬氨酸水平相关来检查谷氨酸能异常的下游后果，N-乙酰天冬氨酸是神经元完整性和功能的标志。在未来的研究中，我们计划确定GLS1基因变异是否与精神疾病存在不同的相互作用，从而在精神分裂症或双相情感障碍患者的队列中产生异常的谷氨酰胺/谷氨酸比率。因此，我们希望通过分子和神经影像分析来探讨精神分裂症和双相情感障碍中谷氨酸能失调的机制。这些研究旨在最终提供两种常见、慢性和严重精神疾病中与谷氨酸能神经传递相关的遗传和化学异常的信息，并通过提供这些异常的特定分子靶点和体内生物标志物来帮助药物开发工作。 公共卫生相关性：精神分裂症和双相情感障碍是两种常见的、慢性和严重的精神疾病，其原因尚不清楚，尽管有重要证据表明，在这些疾病中，关键的大脑化学物质谷氨酸存在异常。在这项提案中，我们将检查与谷氨酸代谢相关的健康人的遗传变异和脑成像指标，并计划在未来将这些研究扩展到精神分裂症或双相情感障碍患者。这项研究项目旨在提供谷氨酸相关大脑测量的新信息，并最终将我们的精神药物开发努力集中在特定的生物靶点上。

DESCRIPTION (provided by applicant): This is an R21 proposal focusing on genetic variation and neuroimaging measures related to brain glutamate metabolism. Glutamate is a crucial neurotransmitter and abnormalities in the glutamate system have been reported in major psychiatric conditions including schizophrenia and bipolar disorder. Indeed, several candidate drugs modifying glutamatergic neurotransmission are under development as treatments for these conditions. This approach holds great promise, but we do not have a good understanding of the molecular determinants of glutamate metabolism or in vivo brain glutamate probes which can support drug development efforts. The PI is an R01 holder from NIMH whose research has focused on optimizing proton magnetic resonance spectroscopy (MRS) sequences for brain glutamate and glutamine quantification and on using MRS to probe regional glutamate dynamics in patient populations. He has recently begun collaborating with Dr. Jordan Smoller, a recognized expert on psychiatric genetics. This collaboration has resulted in recently published data indicating a relationship between variation in the glutaminase (the enzyme which converts glutamine to glutamate) gene GLS1 and the brain glutamine/glutamate ratio measured using MRS. Thus, genetic variation in GLS1 is associated with in vivo variation in the metabolite levels which GLS1 controls. Armed with a validated neuroimaging approach which allows us to quantify in vivo brain glutamate dynamics, we can now experimentally test this hypothesis in an adequately-powered healthy control sample. In Specific Aim 1 of this proposal, we propose to examine the relationship between variation in the GLS1 gene and regional brain glutamine/glutamate ratio in a sample of healthy control subjects. In Specific Aim 2, we will examine downstream consequences of glutamatergic abnormalities by testing whether GLS1 genetic variation is associated with levels of N-acetylaspartate, a marker of neuronal integrity and function. In future studies, we plan to determine whether GLS1 genetic variation interact differentially with psychiatric illness to generate abnormal glutamine/glutamate ratios in cohorts of patients with schizophrenia or bipolar disorder. Thus, we hope to explore the mechanisms of glutamatergic dysregulation in schizophrenia and bipolar disorder through molecular and neuroimaging analyses. These studies are designed to ultimately provide information about genetic and chemical abnormalities related to glutamatergic neurotransmission in two common, chronic, and severe psychiatric disorders and to aid drug development efforts by providing specific molecular targets and in vivo biomarkers of these abnormalities. PUBLIC HEALTH RELEVANCE: Schizophrenia and bipolar disorder are two common, chronic, and severe psychiatric conditions whose causes are poorly understood although significant evidence points to abnormalities in the crucial brain chemical glutamate in these conditions. In this proposal, we will examine genetic variation and brain imaging measures related to glutamate metabolism in healthy people with plans to extend these studies to those with schizophrenia or bipolar disorder in the future. This research project is designed to provide new information on glutamate-related brain measures and ultimately to focus our psychiatric drug development efforts on specific biological targets.