Neuron Subtype and Circuit Specific Patterns of Gene Expression in Schizophrenia

描述(申请人提供)：此申请是对NIMH挑战领域(08)基因组学，挑战主题08-MH-102，精神分裂症互动组的回应。精神分裂症是一种毁灭性的精神疾病，影响着美国和世界各地的数百万人，造成巨大的人力和经济代价。虽然有治疗这种疾病的方法可以缓解一些症状，但没有治愈方法，而且目前使用的药物往往会产生严重的不良副作用。因此，迫切需要新的方法来诊断和治疗这种疾病。在过去的几年里，一些新的基因产物和通路被发现，这表明神经传递的细胞生物学具有更高的复杂性，导致了许多参与精神分裂症病理生理学的候选基因。此外，一些研究人员认为精神分裂症是一种边缘回路障碍，虽然研究这种疾病中基于回路的异常的方法已经开发和验证，但许多项目还没有充分认识到这些工具的潜力。我们建议在精神分裂症患者和对照组的大脑中测量与神经传递相关的~100个候选基因的表达，这些基因以前在基因阵列和其他使用死后脑材料的研究中被确定。我们将使用激光捕获显微镜(LCM)从多个相互连接的脑区采集单个神经元，从而在皮质-纹状体-丘脑回路的背景下测量这些候选基因在确定的神经元亚群中的表达，该回路被假设为这种疾病的许多病理生理学特征的底物。这一挑战领域满足了几个关键需求。从科学上讲，它提供了一个难得的机会来确定一组令人兴奋的神经递质相关候选基因的基因表达模式的分子遗传指纹，这些候选基因位于与边缘回路相关的大脑区域的特定神经元群体中。这些数据将允许测试精神分裂症中这些基因在特定神经元亚群和边缘回路中表达异常的假说。此外，这项工作是劳动密集型的，有助于在经济复苏期间的规定时期创造新的就业机会。阿拉巴马大学伯明翰分校(UAB)是阿拉巴马州最大的雇主，在该大学和医疗系统拥有超过1.8万名教职员工，负责该大学和社区内52,900个相当于全职工作的工作。伯明翰地区每100个工作岗位中有8个与UAB有关，阿拉巴马州每100个工作岗位中有2.8个工作岗位与UAB有关。UAB对伯明翰大都市区的整体经济影响每年超过30亿美元。与ARRA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大脑功能的关键要素。精神分裂症潜在分子成分的识别将为治疗这种疾病的药物开发提供新的靶点。

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.