Identifying molecular path of behavioural phenotype in schizophrenia

描述（由申请人提供）：几种行为/神经生理异常被提议作为替代临床表型标记精神分裂症的责任。这些中间表型可能标志着疾病风险的亚组分和更具体的生化途径，有助于精神分裂症的病因学。一种高度可重复的表型是平滑追求眼动（SPEM，也称为眼球追踪）异常，被50多个研究重复，几乎没有阴性结果。在进化上，这种表型是独特的，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理解还缺乏知识，这在很大程度上是由于这种表型的进化特征，这限制了小动物模型的发展。挑战在于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，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中SPEM缺陷的分子机制。最近的研究表明，预测性追求缺陷（PPD）可能是精神分裂症患者眼球追踪异常的基础。预测追求是灵长类动物维持平稳追求的主要机制。影像学研究已经确定了精神分裂症中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期间前额眼场（FEF）的激活减少。该地区将是拟议研究的重点。预测性追求缺陷存在于精神分裂症患者和一些一级亲属中。至关重要的是，检查这种精致表型的家庭研究揭示了高度的亲切性。这种高度熟悉性允许合理的机会通过在在世的家庭成员中使用代理测量来识别与PPD更均匀相关的死后组织。结合从功能影像学和家族研究中获得的知识，我们计划选择亚表型特异性死后脑组织，以筛选精神分裂症中与PPD相关的转录本。精神分裂症是一种毁灭性的脑部疾病，影响了1%的人口。对于与此病相关的核心生理和认知缺陷缺乏有效的治疗。该项目旨在识别与精神分裂症中一种称为眼球追踪异常的核心缺陷相关的基因和基因产物，以便开发药物来治疗这些核心生理和认知缺陷。

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.