Genetics of Glutamatergic Neurotransmission

描述（由申请人提供）：这是一项R21提案，重点关注与脑谷氨酸代谢相关的遗传变异和神经影像学指标。谷氨酸是一种重要的神经递质，谷氨酸系统的异常已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报道。事实上，几个候选药物修改amatergic神经传递正在开发作为治疗这些条件。这种方法有很大的希望，但我们没有很好地了解谷氨酸代谢的分子决定因素或体内脑谷氨酸探针，可以支持药物开发工作。PI是NIMH的R01保持器，其研究重点是优化质子磁共振波谱（MRS）序列以进行脑谷氨酸和谷氨酰胺定量，以及使用MRS探测患者人群中的局部谷氨酸动力学。他最近开始与公认的精神病遗传学专家乔丹·斯莫勒博士合作。这种合作导致最近发表的数据表明，在谷氨酰胺酶（酶，将谷氨酰胺转化为谷氨酸）基因GLS 1和脑谷氨酰胺/谷氨酸比使用MRS测量的变化之间的关系。因此，GLS 1的遗传变异与GLS 1控制的代谢物水平的体内变化。有了一种经过验证的神经成像方法，使我们能够量化体内脑谷氨酸动力学，我们现在可以在一个足够强大的健康对照样本中实验性地测试这一假设。在本提案的具体目标1中，我们建议在健康对照受试者样本中检查GLS1基因变异与局部脑谷氨酰胺/谷氨酸盐比值之间的关系。在具体目标2中，我们将通过测试GLS 1遗传变异是否与N-乙酰天冬氨酸（神经元完整性和功能的标志物）水平相关来检查谷氨酸能异常的下游后果。在未来的研究中，我们计划确定GLS 1基因变异是否与精神疾病差异相互作用，以在精神分裂症或双相情感障碍患者队列中产生异常的谷氨酰胺/谷氨酸盐比值。因此，我们希望通过分子生物学和神经影像学分析来探讨精神分裂症和双相情感障碍患者的神经递质失调机制。这些研究的目的是最终提供有关两种常见的慢性和严重精神疾病中与多巴胺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。

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.