A Genetic and PET Imaging Study of a Schizophrenia Endophenotype

精神分裂症内表型的遗传和 PET 成像研究

• 批准号: 8076767
• 负责人: IKWUNGA WONODI
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-25 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076767
• 关键词: Alleles; Area; Axon; Behavior; Binding; Biochemistry; Biological Markers; Biological Markers; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Dopamine; Eye; First Degree Relative; Future; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genotype; Goals; Heritability; Human; Image; Impairment; Indium; Individual; Measures; Mediating; Messenger RNA; Methodology; Midbrain structure; Minisatellite Repeats; Minority Groups; Molecular; Monkeys; Neurocognitive Deficit; Parietal; Parietal Lobe; Participant; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Pilot Projects; Positron-Emission Tomography; Prefrontal Cortex; Process; Proteins; Regulator Genes; Relative (related person); Risk; Sampling; Schizophrenia; Secondary to; Signal Pathway; Signal Transduction; Smooth Pursuit; Substantia nigra structure; Symptoms; Synapses; System; Temporal Lobe; Testing; Tissues; Tracer; Transcript; Translating; Up-Regulation; caudate nucleus; density; disease phenotype; disorder risk; dopamine transporter; endophenotype; ethnic minority population; extracellular; frontal eye fields; frontal lobe; functional genomics; in vivo; insight; interest; mRNA Expression; neural circuit; neuroimaging; neuronal cell body; neurophysiology; neurotransmission; predictive pursuit; protein function; public health relevance; radioligand; radiotracer; response; trait

DESCRIPTION (provided by applicant): Schizophrenia has a significant genetic risk. However, the specific genes that contribute to the disease phenotype have not been identified. Our alternative approach is to simplify the problem by using well-defined neurophysiological/cognitive traits that have increased genetic component and are expected to mark sub- components of disease risk and hence, specific molecular pathways between gene variants and translated protein/function8. Smooth pursuit eye movement (SPEM, also called eye tracking) abnormality is an established biological marker for schizophrenia. SPEM deficits have been consistently reproduced in over 60 studies of schizophrenia, with few negative results9. Focusing on SPEM can potentially provide new insights into the etiopathophysiology of schizophrenia. The challenge is to decompose this phenotype into its elemental molecular components in order to determine the paths leading from genes to signaling pathways to behaviors, and to schizophrenia. Studies suggest that deficits in predictive pursuit gain (a subcomponent of SPEM) may underlie the eye tracking impairment in schizophrenia patients and their first-degree relatives. The predictive pursuit gain measure is more sensitive in defining at-risk individuals than traditional SPEM measures10-12. Neuroimaging studies have identified several cortical regions associated with SPEM deficits in schizophrenia. The most consistently replicated finding has been, reduced activation in the frontal eye fields (FEF) during SPEM13-15. Although the FEF is the primary cortical area for the control of SPEM, recent studies have shown that FEF control of SPEM is effected through several descending pathways. This functional neural circuitry of the pursuit system consists of a cortico-striato-pallido-thalamo-cortical loop distributed through the midbrain, temporal, parietal, and prefrontal cortices16-18. Emerging evidence from monkeys and humans has established dense efferent projections from the FEF to the caudate nucleus and substantia nigra, and that these relay stations are critical in the neuromotor and cognitive processes that control predictive pursuit19-21. Thus, the FEF and the caudate are regions of interest in the proposed pilot study. Dysregulation of dopamine signaling, particularly in the prefrontal cortex, is considered to be at the core of several neurocognitive deficits in schizophrenia22. Overlapping components of the predictive pursuit circuitry are modulated by dopaminergic neurotransmission, including the FEF and caudate23;24. This proposal will examine the relationship between eye tracking and the density of the dopamine transporter (DAT) in the FEF and caudate in schizophrenia and healthy controls. A second focus will be on the effect of a functional variable number of tandem repeats (VNTR) polymorphism in the dopamine transporter gene (DAT1) and DAT density in the FEF and caudate. DAT density is measured by the binding potential of the DAT-specific radioligand, [11C]WIN 35,428, during Positron Emission Tomography (PET) scan. The study's approach integrates ex vivo molecular biochemistry, functional genomics, and in vivo neuroimaging methodologies. PUBLIC HEALTH RELEVANCE: A pilot study to examine the relationship between a heritable schizophrenia biomarker (eye tracking), DAT1 genotype, and the dopamine transporter density using PET radiotracer imaging.

描述（由申请人提供）：精神分裂症具有显著的遗传风险。然而，导致疾病表型的特定基因尚未被鉴定。我们的替代方法是通过使用定义明确的神经生理学/认知特征来简化问题，这些特征具有增加的遗传成分，并有望标记疾病风险的子成分，从而标记基因变体和翻译蛋白质/功能之间的特定分子途径8。平滑追踪眼球运动（SPEM，也称为眼动追踪）异常是精神分裂症的一个既定生物学标志。在60多项精神分裂症的研究中，SPEM缺陷一直在重现，很少有阴性结果9。关注SPEM可能为精神分裂症的病因病理生理学提供新的见解。挑战在于将这种表型分解成其基本分子组分，以确定从基因到信号通路到行为和精神分裂症的路径。研究表明，预测追踪增益（SPEM的一个子成分）的缺陷可能是精神分裂症患者及其一级亲属眼跟踪障碍的基础。预测性追求增益测量在定义风险个体方面比传统SPEM测量更敏感10 -12。神经影像学研究已经确定了精神分裂症患者与SPEM缺陷相关的几个皮层区域。最一致的重复发现是，SPEM 13 -15期间额叶眼区（FEF）的激活减少。虽然FEF是控制SPEM的主要皮层区域，但最近的研究表明，FEF对SPEM的控制是通过几条下行通路实现的。这种追踪系统的功能性神经回路由分布在中脑、颞叶、顶叶和前额皮质的皮质-纹状体-苍白球-丘脑-皮质回路组成16 -18。来自猴子和人类的新证据已经建立了从FEF到尾状核和黑质的密集传出投射，并且这些中继站在控制预测追求的神经运动和认知过程中至关重要19 -21。因此，FEF和尾状核是拟议的初步研究中感兴趣的区域。多巴胺信号的失调，特别是在前额叶皮层，被认为是精神分裂症中几种神经认知缺陷的核心22。预测追踪电路的重叠组件由多巴胺能神经传递调制，包括FEF和尾状核23;24。本研究将探讨精神分裂症患者和健康对照者的FEF和尾状核中多巴胺转运蛋白（DAT）密度与眼动追踪之间的关系。第二个重点将是多巴胺转运蛋白基因（DAT 1）和DAT密度在FEF和尾状核的功能可变数目的串联重复序列（VNTR）多态性的影响。在正电子发射断层扫描（PET）扫描期间，通过DAT特异性放射性配体[11 C]WIN 35，428的结合潜力来测量DAT密度。这项研究的方法整合了体外分子生物化学，功能基因组学和体内神经成像方法。 公共卫生相关性：一项使用PET放射性示踪剂成像检查遗传性精神分裂症生物标志物（眼动追踪）、DAT 1基因型和多巴胺转运蛋白密度之间关系的初步研究。