MRS Studies of Glutamate and GABA in Bipolar Dissorder

描述（由申请人提供）：这是K23指导的以患者为导向的研究职业发展奖申请的第一次重新提交，题为“双相情感障碍中谷氨酸和GABA的MRS研究”。候选人的背景是在双相情感障碍（BD）细胞异常的尸检研究，他目前是姆克林医院精神分裂症和双相情感障碍项目的主任。目前的提案旨在允许候选人使用体内神经成像来扩展其BD细胞异常的发现。磁共振波谱（MRS）是一种非常好的技术，候选人选择在佩里伦肖博士的指导下工作，他是一位领先的MRS专家，也是姆克林脑成像中心的主任。鉴于他直接参与BD患者的临床护理以及与领先的MRS研究小组的关系，该候选人有能力开发一个将MRS方法应用于BD研究的独立研究项目。希望这将导致更好地了解BD的病理生理学和目前的治疗方法，以及识别新的治疗靶点。拟议研究的主要目标是使用最近开发的MRS方法来量化BD患者和健康对照组的脑谷氨酸和γ-氨基丁酸（GABA）水平。谷氨酸和GABA是大脑中最丰富的神经递质，它们的功能需要广泛的神经元-胶质细胞相互作用。因此，它们的水平提供了突触功能和细胞活动的信息。该应用的中心假设是BD中的细胞异常将系统地反映在谷氨酸和GABA异常中。将在BD中报告异常的前扣带皮层和顶枕皮层中测量谷氨酸盐和GABA水平。候选人将利用其从BD专业临床单位招募患者的能力，检查疾病阶段（复发与首次发作）和疾病发作（两个队列中躁狂和抑郁发作的患者，以及药物和无药物的心境正常门诊患者）对测量的影响。将进行统计分析，以检查这些因素对谷氨酸和GABA水平的影响。作为拟议研究的一部分，候选人寻求以下方面的培训：1）MRS数据分析的MRS技术和方法; 2）突触传递和细胞代谢的神经化学; 3）伦理临床研究方法。拟议的研究计划，教学课程，并与导师和顾问的工作将促进候选人的发展成为一个独立的临床医生，科学家使用神经影像学研究BD神经化学。BD是一种常见的使人衰弱的疾病。目前的BD治疗是部分有效的，其作用机制还不清楚。因此，迫切需要针对BD中相关生物过程的有效新型治疗方法，目前的提案旨在满足这一需求。

DESCRIPTION (provided by applicant): This is a first resubmission of a K23-Mentored Patient-Oriented Research Career Development Award application entitled "MRS Studies of Glutamate and GABA in Bipolar Disorder". The candidate's background is in postmortem studies of cellular abnormalities in bipolar disorder (BD), and he is currently the Director of the Schizophrenia and Bipolar Disorder Program at McLean Hospital. The current proposal is designed to allow the candidate to use in vivo neuroimaging to extend his findings of cellular abnormalities in BD. Magnetic resonance spectroscopy (MRS) is an excellent technique for this purpose, and the candidate has chosen to work under the mentorship of Dr. Perry Renshaw, a leading MRSexpert and director of McLean's Brain Imaging Center. Given his direct involvement in the clinical care of patients with BD and relationship with a leading MRS research group, the candidate is well-positioned to develop an independent research program applying MRS approaches to BD studies. It is hoped that this will lead to a better understanding of BD pathophysiology and current treatments, as well as to identification of novel treatment targets. The main goal of the proposed research is to use recently developed MRS approaches to quantify brain glutamate and gamma-aminobutyric-acid (GABA) levels in BD patients and healthy controls. Glutamate and GABA are the most abundant neurotransmitters in the brain, and extensive neuronal-glial interactions are required for their function. Their levels therefore provide information on synaptic function and cellular activity. The central hypothesis of the application is that cellular abnormalities in BD will be systemactically reflected in glutamate and GABA abnormalities. Glutamate and GABA levels will be measured in the anterior cingulate cortex where abnormalities have been reported in BD, and in the parieto-occipital cortex. The candidate will take advantage of his ability to recruit patients from a clinical unit specializing in BD to examine the effects of phase of illness (recurrent vs. first-episode) and disease episode (patients in manic and depressive episodes in both cohorts, as well as medicated and medication-free euthymic outpatients) on the measures. Statistical analyses will be tailored to examine the effects of these factors on glutamate and GABA levels. As part of proposed research, the candidate seeks training in: 1) MRS techniques and methods for MRS data analysis; 2) neurochemistry of synaptic transmission and cellular metabolism; and 3) ethical clinical research methods. The proposed research plan, didactic courses, and work with mentors and advisors will foster the candidate's development into an independent clinician-scientist using neuroimaging to study BD neurochemistry. BD is a common and debilitating illness. Current BD treatments are partially effective, and their mechanisms of action are not well-understood. There is therefore a pressing need for effective novel treatments which target relevant biological processes in BD, and the current proposal aims to contribute to meeting this need.