Neuron Subtype and Circuit Specific Patterns of Gene Expression in Schizophrenia

描述（由申请人提供）：本申请是对NIMH挑战区（08）基因组学，挑战主题08-MH-102，精神分裂症相互作用组的回应。精神分裂症是一种毁灭性的精神疾病，影响着美国和全世界数百万人，造成了巨大的人力和经济损失。虽然有治疗这种疾病的方法可以改善一些症状，但没有治愈方法，目前使用的药物通常具有显著的不良副作用。因此，非常需要新的方法来诊断和治疗这种疾病。在过去的几年中，已经确定了一些新的基因产物和途径，指向神经传递的细胞生物学的更高水平的复杂性，导致许多候选基因参与精神分裂症的病理生理学。此外，许多研究人员认为精神分裂症是边缘系统回路的紊乱，虽然已经开发和验证了研究这种疾病中基于回路的异常的方法，但许多项目尚未实现这些工具的全部潜力。我们建议在患有精神分裂症的人和对照组的大脑中测量与神经传递相关的约100个候选基因的表达，这些基因先前已在基因阵列和其他使用死后大脑材料的研究中确定。我们将使用激光捕获显微镜（LCM）收获单个神经元从多个相互连接的大脑区域，从而测量这些候选基因的表达在定义的神经元亚群内的皮质-纹状体-丘脑电路的上下文中假设是这种疾病的病理生理学的许多功能的基板。这一挑战领域满足了若干关键需求。科学上，它提供了一个难得的机会，以确定一组令人兴奋的神经递质相关的候选基因的基因表达模式的分子遗传指纹在定义的神经元群体与边缘系统电路相关的大脑区域。这些数据将允许测试这些基因在特定的神经元亚群和边缘回路内的表达在精神分裂症中异常的假设。此外，这项工作是劳动密集型的，有助于在经济复苏期间创造新的就业机会。伯明翰亚拉巴马大学（UAB）是亚拉巴马最大的雇主，在大学和卫生系统拥有18，000多名教职员工，并负责大学和社区内的52，900个全职等效工作。伯明翰地区每100个工作岗位中有8个，亚拉巴马每100个工作岗位中有2.8个与UAB有关。UAB在伯明翰都会区的整体经济影响每年超过30亿美元。与ARRA的目标一致，此应用程序将创建或保留四个全职和一个兼职工作。 公共卫生相关性：该项目将确定有助于精神分裂症病理生理学的脑功能的关键要素。鉴定精神分裂症的分子基础将为开发治疗这种疾病的药物提供新的靶点。

DESCRIPTION (provided by applicant): This application is in response to NIMH Challenge Area (08) Genomics, Challenge Topic 08-MH-102, Schizophrenia Interactome. Schizophrenia is a devastating mental illness affecting millions in the US and worldwide, with profound human and economic costs. While there are treatments for this illness that ameliorate some of the symptoms, there is no cure and the medications currently in use often have significant unwanted side effects. Thus, there is tremendous need for new approaches for the diagnosis and treatment of this illness. Over the past few years, a number of novel gene products and pathways have been identified pointing to a higher level of complexity of the cell biology of neurotransmission, resulting in numerous candidate genes for involvement in the pathophysiology of schizophrenia. In addition, a number of investigators consider schizophrenia a disorder of limbic circuitry, and while methods to study circuit- based abnormalities in this illness have been developed and validated, many projects have not realized the full potential of these tools. We propose to measure in brains of persons that had schizophrenia and a comparison group the expression of ~100 candidate genes associated with neurotransmission that have previously been identified in gene array and other studies using postmortem brain material. We will use laser capture microscopy (LCM) to harvest individual neurons from multiple interconnected brain regions, thus measuring expression of these candidate genes in defined neuronal subpopulations within the context of the cortico-striato-thalamic circuitry hypothesized to be a substrate for many features of the pathophysiology of this illness. This challenge area meets several critical needs. Scientifically, it provides a rare opportunity to determine the molecular genetic fingerprint of patterns of gene expression of an exciting set of neurotransmitter-related candidate genes in defined neuronal populations with brain regions associated with limbic circuitry. These data would permit the testing of hypotheses of abnormalities in schizophrenia of expression of these genes in specific subsets of neurons and within limbic circuits. In addition, this work is labor-intensive and facilitates creation of new employment opportunities for a defined period during this time of economic recovery. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain four full time and one part time job. PUBLIC HEALTH RELEVANCE: This project will identify the critical elements of brain function that contribute to the pathophysiology of schizophrenia. Identification of the molecular elements underlying schizophrenia will provide new targets for the development of medicines to treat this illness.