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: 7991214
• 负责人: IKWUNGA WONODI
• 金额: $ 24.43万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991214
• 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; Participant; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Pilot Projects; Positron-Emission Tomography; Prefrontal Cortex; Process; Proteins; Regulator Genes; Relative (related person); Research; Risk; Sampling; Schizophrenia; Secondary to; Signal Pathway; Signal Transduction; Smooth Pursuit; Substantia nigra structure; Symptoms; Synapses; System; 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）：精神分裂症具有显着的遗传风险。然而，尚未确定导致疾病表型的特定基因。我们的替代方法是通过使用明确的神经生理学/认知特征来简化问题，这些特征增加了遗传成分，并有望标记疾病风险的子成分，从而标记基因变异和翻译蛋白质/功能之间的特定分子途径8。平滑追踪眼球运动（SPEM，也称为眼球追踪）异常是精神分裂症的既定生物学标志。 SPEM 缺陷在 60 多项精神分裂症研究中得到了一致重现，几乎没有负面结果 9。关注 SPEM 可能会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为其基本分子成分，以确定从基因到信号传导途径再到行为和精神分裂症的路径。研究表明，预测性追踪增益（SPEM 的一个组成部分）的缺陷可能是精神分裂症患者及其一级亲属眼动追踪障碍的原因。预测性追求增益测量在定义高危个体方面比传统 SPEM 测量更敏感10-12。神经影像学研究已经确定了与精神分裂症 SPEM 缺陷相关的几个皮质区域。最一致重复的发现是，在 SPEM13-15 期间，额眼视野 (FEF) 的激活减少。虽然 FEF 是控制 SPEM 的主要皮质区域，但最近的研究表明 FEF 对 SPEM 的控制是通过几个下行途径实现的。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-皮质环路组成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，并且这些中继站对于控制预测追踪的神经运动和认知过程至关重要 19-21。因此，FEF 和尾状核是拟议试点研究中感兴趣的区域。多巴胺信号传导失调，特别是前额叶皮层的多巴胺信号传导失调，被认为是精神分裂症多种神经认知缺陷的核心22。预测追踪电路的重叠部分由多巴胺能神经传递调节，包括 FEF 和尾状核23;24。该提案将研究精神分裂症和健康对照组的眼球追踪与 FEF 和尾状核中多巴胺转运蛋白 (DAT) 的密度之间的关系。第二个重点是多巴胺转运蛋白基因 (DAT1) 中功能性可变串联重复次数 (VNTR) 多态性以及 FEF 和尾状核中 DAT 密度的影响。 DAT 密度是通过正电子发射断层扫描 (PET) 扫描期间 DAT 特异性放射性配体 [11C]WIN 35,428 的结合电位来测量的。该研究的方法整合了离体分子生物化学、功能基因组学和体内神经影像方法。 公共健康相关性：一项初步研究，旨在使用 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）、DAT1 基因型和多巴胺转运蛋白密度之间的关系。