Identifying molecular path of behavioural phenotype in schizophrenia

描述(由申请人提供)：提出了几种行为/神经生理异常作为临床表型的替代，以标记精神分裂症的易感性。这些中间表型可能标志着疾病风险的亚组分，以及导致精神分裂症病因学的更具体的生化途径。一种高度可重复性的表型是平滑追踪眼球运动(SPEM，也称为眼球跟踪)异常，50多项研究重复了这一异常，但几乎没有负面结果。在进化上，这种表型是独一无二的，因为SPEM是一种只存在于灵长类动物的行为。不幸的是，到目前为止，我们对异常眼动的分子基础的了解仍然是空白的，这主要是由于这种表型的进化特征，这限制了小动物模型的发展。挑战是如何将这种独特的表型转化为有形的生化研究，这是描述从基因到行为缺陷的途径并从而建立新的分子治疗靶点的必要步骤。我们已经开发了一种策略，使我们能够探索精神分裂症患者SPEM缺陷的分子机制。最近的研究表明，预测性追踪缺陷(PPD)可能是精神分裂症令人瞠目的异常的基础。预测性追逐是灵长类动物维持顺畅追逐的主要机制。影像研究已经确定了精神分裂症患者SPEM缺陷的几个候选解剖位点。在这些基因座中，一致重复的发现是在SPEM期间额叶眼场(FEF)的激活减少。这一区域将是拟议研究的重点。精神分裂症患者及部分一级亲属存在预测性追求缺陷。关键的是，对这种精致表型的家庭研究显示出高度的熟悉性。这种高度的熟悉度使得有合理的机会使用代理测量方法在活着的家庭成员中识别与PPD更同质性的死后组织。结合从功能成像和家族研究中学到的知识，我们计划选择特定于亚型的死后脑组织，以筛选与精神分裂症的PPD相关的转录本。精神分裂症是一种毁灭性的脑部疾病，影响着我们1%的人口。缺乏对与这种疾病相关的核心生理和认知缺陷的有效治疗。该项目旨在确定与精神分裂症中这些核心缺陷之一--眼睛跟踪异常--相关的基因和基因产品，以便开发治疗这些核心生理和认知缺陷的药物。

DESCRIPTION (provided by applicant): Several behavioral/neurophysiological abnormalities are proposed as alternatives to the clinical phenotype in marking the liability for schizophrenia. These intermediate phenotypes may mark sub-components of disease risk and more specific biochemical paths contributing to the etiology of schizophrenia. One highly reproducible phenotype is the smooth pursuit eye movement (SPEM, also called eyetracking) abnormality, replicated by over 50 studies with few negative results. Evolutionally this phenotype is unique in that SPEM is a behavior only present in primates. Unfortunately until now there is a void of knowledge in our understanding of the molecular basis of abnormal eyetracking, largely due to the evolutionary characteristics of this phenotype, which limits the development of small animal models. The challenge is how this unique phenotype can be translated into tangible biochemical studies, which is a necessary step to describe the path from genes to behavioral deficits and thereby to establish new molecular treatment targets. We have developed a strategy that allows us to probe the molecular mechanisms of SPEM deficits in schizophrenia. Recent studies suggest that predictive pursuit deficit (PPD) may underlie the eyetracking abnormality in schizophrenia. Predictive pursuit is the primary mechanism for maintaining smooth pursuit in primates. Imaging studies have identified several candidate anatomic loci of the SPEM deficit in schizophrenia. Among these loci, the consistently replicated finding is reduced activation in the frontal eye fields (FEF) during SPEM. This region will be the focus of the proposed study. Predictive pursuit deficit is present in schizophrenia patients and some 1st degree relatives. Critically, family studies examining this refined phenotype revealed a high familiality. The high familiality permits a reasonable chance to identify postmortem tissues more homogenously associated with PPD using proxy measurement in living family members. Combining knowledge learned from functional imaging and family studies, we plan to select subphenotype-specific postmortem brain tissue for the purpose of screening transcripts associated with PPD in schizophrenia. Schizophrenia is a devastating brain illness affecting 1% of our population. There is lack of effective treatment for core physiological and cognitive deficits associated with this illness. This project aims to identify genes and gene products associated with one of these core deficits called eyetracking abnormality in schizophrenia so that drugs can be developed to treat these core physiological and cognitive deficits.