Characterization of Genetic Mechanisms Contributing to Neuropsychiatric Disorder

导致神经精神疾病的遗传机制的特征

• 批准号: 8556974
• 负责人: Karen FAITH Berman
• 金额: $ 301.62万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556974
• 关键词: AKT1 gene; Affect; Alleles; Amphetamines; Animal Model; Antipsychotic Agents; Apoptosis; Arousal; Autopsy; Axon; Behavior; Behavioral; Binding; Bioinformatics; Biological; Biological Assay; Biological Models; Biology; Brain; Brain Diseases; C-terminal; COMT gene; Candidate Disease Gene; Catalytic Domain; Catechols; Cell Death; Cell membrane; Cell model; Cell physiology; Cells; Chromosome Mapping; Clinical; Cognition; Cognitive; Collaborations; Complex; Computer Simulation; DNA; Data; Data Set; Dendrites; Development; Diagnosis; Disease; Dopamine; Dose; Drug Delivery Systems; Emotional; Environmental Risk Factor; Enzymes; ErbB4 gene; Etiology; Europe; European; Extracellular Space; Family; Female; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; German population; Glutamine; Human; Human Genetics; IC 87114; Image; Impaired cognition; Institutes; Knockout Mice; Laboratories; Laws; Learning; Lesion; Libido; Life; Literature; Measures; Mediating; Membrane; Methods; Mission; Modeling; Molecular; Molecular Target; Mus; NRG1 gene; Neurobiology; Neurons; Neuropsychology; Neurosciences; Online Systems; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Population; Predisposition; Prevention; Process; Proteins; Psychotic Disorders; Publishing; Rattus; Reporting; Research; Research Personnel; Resources; Risk; Rodent Model; Role; Sample Size; Sampling; Schizophrenia; Scientist; Signal Pathway; Signal Transduction; Stress; Structure; Surface; Susceptibility Gene; Symptoms; Synapses; System; Testing; Therapeutic; Toxic effect; Transcript; Transgenic Mice; Translating; United States National Institutes of Health; Variant; Work; base; case control; clinical Diagnosis; clinical phenotype; cognitive function; cohort; cytotoxicity; disorder risk; drug sensitivity; gene function; gene interaction; genetic association; genetic variant; genome wide association study; inhibitor/antagonist; lymphoblast; mRNA Expression; meetings; microdeletion; molecular pathology; mouse model; neurobiological mechanism; neurodevelopment; neuroimaging; neuronal cell body; neuropsychiatry; neuropsychological; neurotransmission; novel; postsynaptic; programs; relating to nervous system; sex; therapeutic target; tolcapone; transmission process; trend; valylvaline; AKT1 gene; Affect; Alleles; Amphetamines; Animal Model; Antipsychotic Agents; Apoptosis; Arousal; Autopsy; Axon; Behavior; Behavioral; Binding; Bioinformatics; Biological; Biological Assay; Biological Models; Biology; Brain; Brain Diseases; C-terminal; COMT gene; Candidate Disease Gene; Catalytic Domain; Catechols; Cell Death; Cell membrane; Cell model; Cell physiology; Cells; Chromosome Mapping; Clinical; Cognition; Cognitive; Collaborations; Complex; Computer Simulation; DNA; Data; Data Set; Dendrites; Development; Diagnosis; Disease; Dopamine; Dose; Drug Delivery Systems; Emotional; Environmental Risk Factor; Enzymes; ErbB4 gene; Etiology; Europe; European; Extracellular Space; Family; Female; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; German population; Glutamine; Human; Human Genetics; IC 87114; Image; Impaired cognition; Institutes; Knockout Mice; Laboratories; Laws; Learning; Lesion; Libido; Life; Literature; Measures; Mediating; Membrane; Methods; Mission; Modeling; Molecular; Molecular Target; Mus; NRG1 gene; Neurobiology; Neurons; Neuropsychology; Neurosciences; Online Systems; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Population; Predisposition; Prevention; Process; Proteins; Psychotic Disorders; Publishing; Rattus; Reporting; Research; Research Personnel; Resources; Risk; Rodent Model; Role; Sample Size; Sampling; Schizophrenia; Scientist; Signal Pathway; Signal Transduction; Stress; Structure; Surface; Susceptibility Gene; Symptoms; Synapses; System; Testing; Therapeutic; Toxic effect; Transcript; Transgenic Mice; Translating; United States National Institutes of Health; Variant; Work; base; case control; clinical Diagnosis; clinical phenotype; cognitive function; cohort; cytotoxicity; disorder risk; drug sensitivity; gene function; gene interaction; genetic association; genetic variant; genome wide association study; inhibitor/antagonist; lymphoblast; mRNA Expression; meetings; microdeletion; molecular pathology; mouse model; neurobiological mechanism; neurodevelopment; neuroimaging; neuronal cell body; neuropsychiatry; neuropsychological; neurotransmission; novel; postsynaptic; programs; relating to nervous system; sex; therapeutic target; tolcapone; transmission process; trend; valylvaline

Researchers in this group identify a potential therapeutic target for the treatment of Schizophrenia, a debilitating disorder affecting approximately 1% of the population. This year the neurobiology group published data describing genetically regulated signaling pathways involving NRG1-ErbB4 and the PI3K enzyme, p110 all of which are associated with risk for schizophrenia. Law et al (PNAS 2012) show that pharmacological inhibition of p110 blocks behavioral effects of amphetamine in a mouse model of psychosis and reverses schizophrenia-like phenotypes in a neurodevelopmental rat lesion model. The p110 inhibitor, IC87114, has been shown to increase phosphorylation in another SZ risk gene, AKT1 in the brain of treated mice which is consistent with other antipsychotic-like molecules and suggests a mechanism of action. NRG1 and ErbB4 are known to be critical in neurodevelopment, brain plasticity. Previous reports from our lab and others have shown genetic mutations in NRG1 to be associated with risk for SZ, likewise genetic variation and structural microdeletions in ErbB4 also impacts risk for illness. While NRG1 and ErbB4 null mice show behavioral patterns consistent with other SZ mouse models, human postmortem SZ brains also show an increase in NRG1 and ErbB4 expression. Genetic variations in these genes affects human brain structure and function, but the mechanisms of how these changes turns into illness remain unknown. Enzyme p110, also related to SZ can act in concert with NRG1/ErbB4 pathways downstream and has been shown in studies of lymphoblasts from patients, where there is an increase in enzyme levels. Additionally, in human SZ brain there is an increase in enzyme expression. It appears NRG1 and ErbB4 could be potential therapeutic targets however they play roles in cell physiology making them unlikely candidates for targeting. The better choice, P110 which operates downstream of NRG1/ErbB4 may prove to be targetable and provide optimum therapeutic potential. Investigators in the Genetics and Bioinformatics Core Laboratory continues to identify novel SZ susceptibility genes and characterize their mechanism of action in both normal and diseased states. Our clinical, postmortem DNA and phenotype datasets are organized for efficient analysis using web-based family transmission and case-control methods. Genetic variants, genotypes, and statistical genetics results are shared with various phenotyping groups, including investigators in the Clinical Neuropsychology, and Neuroimaging Core Lab, investigators in the postmortem section and in our other research labs investigating risk genes and their biological impact. We select and prioritize functional and positional candidate genes based on the literature, in silico searches of interacting protein networks, and on new findings from ongoing collaborations. We also continue to identify and genotype variations in existing candidate genes and tests them for association with SZ, intermediate phenotypes from the Clinical Brain Disorders Branch, and expression phenotypes in human postmortem brain, cellular and animal model systems. This past year Zhang et al (Biol Psych 2011) performed association studies in 4 cohorts of European ancestry of a newly identified SNP (rs7597593) in ZNF804A, a previously described risk gene for SZ. We measured the SNP effect on mRNA expression using postmortem human brain. Since GWAS are generally used to identify common genetic variations in common diseases but less successful for identifying genetic variants in complex illnesses, like SZ, our study provides supportive evidence of an association of rs7597593 with risk for SZ that is also female-driven. A trend of sex-SNP interaction is seen in both, the combined 4 samples and US Gain cohort, the largest of all the samples. Risk association was seen at the level of clinical risk and in postmortem brain mRNA expression. Association and the sex-driven effect on risk were observed in 3 of the 4 cohorts (German, Scottish and US GAIN) individually as well as in the combined 4 case-control cohort sample, but statistical significance is not seen in the CBDB US cohort, whose limitation was more than likely sample size. To date, the function of the ZNF804A gene remains unknown. The results of the mRNA expression in postmortem brain and the sex-driven association of ZNF804A suggest a molecular mechanism between sex and rs7597593 on risk. Based on this study we are unable to ascribe causation to these genetic associations therefore additional studies of gene-gene interactions may help reveal the mechanism through which ZNF804A genetic variants affect risk for disease. Another group is our Transgenic Mouse and Cellular Models Lab, which translates human genetic mutations into genetic mouse models as an important strategy to study the pathogenesis of schizophrenia, identify potential drug targets, and tests new drugs for antipsychotic treatments. It is certainly impossible to capture the full spectrum of schizophrenia symptoms in animal models and as mentioned earlier in the Law, PNAS article rodent models have been successful in reproducing several schizophrenia-like behaviors and uncovering the roles of specific genes in dopamine and glutamine neurotransmission systems in mediating schizophrenia-like behaviors. Discoveries of susceptibility genes for schizophrenia and targeting cognitive dysfunction as a core feature of the disorder, provides the opportunity to develop and test newer genetic mouse models based on susceptibility. Although genetic mouse models based on genetic susceptibility are relatively new, we continue to study the roles of susceptibility genes in cognitive processing, neuronal function, and signal transduction in the brain during development. Examining candidate risk genes interactions with environmental factors, will most likely give us a better understanding of the molecular mechanisms of the pathophysiology of schizophrenia, reveal the molecular basis of normal cognitive function and human brain development, and guide us to novel antipsychotic therapies. Lastly, we look at how gene COMT relate to the biology and potential treatment of schizophrenia. The Transgenic Mouse and Cellular Models Lab explored the orientation and cellular distribution of Membrane-bound COMT. As been previously noted, COMT is a schizophrenia risk gene and a key enzyme for inactivating and metabolizing catechols, like dopamine, and plays a role in cognition, arousal, pain sensitivity and stress reactivity in humans and animal models. There are two forms of COMT, soluble (S) and membrane-bound (MB). In brain, MB is prevalent, but its neural cellular distribution and orientation are unclear. Chen et al (J Biol Chem 2011) show that MB is located in the neuron cell body, axons and dendrites in rat brain in addition MB orientation has the C-terminal catalytic domain in the extracellular space. This suggests MB has the capability to inactivate synaptic and extrasynaptic dopamine on the surface of pre-and postsynaptic neurons. We also show that the COMT inhibitor, tolcapone induces cell death via apoptosis and its cytotoxicity is dose dependent and correlated with COMT val/met genotype in human lymphoblasts. These data show that inhibitors impermeable to cell membrane in brain can be developed and for those who show drug sensitivity (COMT val/val genotype), use of low doses on a specific genetic background may ameliorate toxic effects of the drug.

该小组的研究人员确定了治疗精神分裂症的潜在治疗靶标，这是一种影响大约1％人群的使人衰弱的疾病。今年，神经生物学小组发布了描述涉及NRG1-ERBB4和PI3K酶的遗传调节信号通路的数据，P110与精神分裂症的风险有关。 Law等人（PNAS 2012）表明，对P110的药理抑制阻断了苯丙胺在精神病小鼠模型中的行为影响，并逆转神经发育大鼠病变模型中的精神分裂症样表型。 p110抑制剂IC87114已显示出在另一种SZ风险基因中增加磷酸化，即处理的小鼠大脑中的Akt1，这与其他抗精神病药样分子一致，并提出了一种作用机理。已知NRG1和ERBB4在神经发育，脑可塑性中至关重要。我们实验室和其他人的先前报告显示，NRG1中的基因突变与SZ的风险有关，ERBB4中的遗传变异和结构性微作用也会影响疾病的风险。虽然NRG1和ERBB4无效的小鼠显示出与其他SZ小鼠模型一致的行为模式，但人类验尸SZ大脑也显示出NRG1和ERBB4表达的增加。这些基因的遗传变异会影响人脑的结构和功能，但是这些变化的机制变成疾病仍然未知。也与SZ相关的酶P110可以与NRG1/ERBB4途径一起起作用，并在酶水平升高的患者的淋巴细胞研究中已显示。此外，在人类SZ脑中，酶表达有所增加。看来NRG1和ERBB4可能是潜在的治疗靶标，但是它们在细胞生理学中起着作用，使它们不太可能靶向靶向。更好的选择，在NRG1/ERBB4下游运行的P110可能被证明是可定位的，并具有最佳的治疗潜力。 遗传学和生物信息学核心实验室中的研究人员继续鉴定出新的SZ敏感性基因，并在正常状态和患病状态下表征其作用机理。我们的临床，验尸DNA和表型数据集是通过基于Web的家庭传播和病例对照方法进行有效分析的。遗传变异，基因型和统计遗传学结果与各种表型组共享，包括临床神经心理学的研究者以及神经影像学核心实验室，后验尸部分的研究者以及我们的其他研究实验室研究风险基因及其生物学影响。我们根据文献，对相互作用的蛋白质网络的硅搜索以及正在进行的合作的新发现来选择并确定功能和位置候选基因。我们还继续识别现有候选基因中的和基因型变化，并测试它们与SZ的关联，临床脑疾病分支的中间表型以及人类后脑大脑，细胞和动物模型系统中的表达表型。去年，Zhang等人（Biol Psych 2011）在ZnF804A的4个新鉴定的SNP（RS7597593）的欧洲血统中进行了关联研究，这是先前描述的SZ风险基因。我们使用后人脑测量了SNP对mRNA表达的影响。由于GWAS通常用于鉴定常见疾病中的常见遗传变异，但在鉴定SZ等复杂疾病中遗传变异方面的遗传变异较少，因此我们的研究提供了RS7597593与女性驱动的SZ风险相关的支持证据。在所有样本中，共有4个样本和美国获得队列中都可以看到性别SNP相互作用的趋势。在临床风险水平和死后脑mRNA表达的水平上，风险关联。在四个队列（德国，苏格兰和美国的收益）以及合计的4个病例对照组样本中，在4个队列中的3个（德国，苏格兰和美国的收益）中观察到了关联和性驱动对风险的影响，但是在CBDB US队列中未见统计学意义，其限制的限制是样本尺寸的可能性高。迄今为止，ZnF804a基因的功能仍然未知。在事后大脑中mRNA表达的结果以及Znf804a的性驱动性关联表明，性别与卢比之间的分子机制有风险。基于这项研究，我们无法将因果关系归因于这些遗传关联，因此基因 - 基因相互作用的其他研究可能有助于揭示Znf804a遗传变异影响疾病风险的机制。 另一组是我们的转基因小鼠和细胞模型实验室，该实验室将人类遗传突变转化为遗传小鼠模型，作为研究精神分裂症发病机理，鉴定潜在药物靶标并测试新药物的抗精神病药物治疗的重要策略。当然，在动物模型中捕捉精神分裂症症状的全部光谱肯定是不可能的，如法律前面提到的那样，PNAS文章啮齿动物模型已成功地繁殖了几种类似精神分裂症的行为，并揭示了特定基因在多巴胺和谷氨酰胺神经胺转化系统中的作用，并在中介化的精神分裂症中介导类精神分裂性行为。精神分裂症的易感基因的发现和靶向认知功能障碍作为该疾病的核心特征，为开发和测试基于易感性的新遗传小鼠模型提供了机会。尽管基于遗传敏感性的遗传小鼠模型相对较新，但我们继续研究易感基因在发育过程中大脑中大脑中认知处理，神经元功能和信号转导的作用。检查候选风险基因与环境因素的相互作用，很可能会使我们对精神分裂症病理生理学的分子机制有更好的了解，这揭示了正常认知功能和人脑发育的分子基础，并指导我们来新颖的抗精神病药疗法。最后，我们研究了基因COMT与精神分裂症的生物学和潜在治疗方法的关系。转基因小鼠和细胞模型实验室探索了膜结合COMT的方向和细胞分布。如前所述，COMT是一种精神分裂症的风险基因，也是一种用于灭活和代谢儿茶酚（如多巴胺）的关键酶，并且在人类和动物模型中在认知，唤醒，疼痛敏感性和压力反应性中起作用。有两种形式的COMT，可溶性（S）和膜结合（MB）。在大脑中，MB很普遍，但其神经细胞分布和方向尚不清楚。 Chen等人（J Biol Chem 2011）表明，MB位于大鼠脑中的神经元细胞体，轴突和树突中，此外，MB方向在细胞外空间中具有C-末端催化结构域。 这表明MB具有在突触前神经元表面上灭活突触和突触外多巴胺的能力。我们还表明，COMT抑制剂Tolcapone通过细胞凋亡诱导细胞死亡，其细胞毒性取决于剂量，并与人淋巴细胞中的COMT Val/MET基因型相关。这些数据表明，可以开发出对大脑细胞膜不渗透的抑制剂，对于表现出药物敏感性的患者（COMT Val/Val基因型），在特定的遗传背景上使用低剂量可能会改善该药物的毒性作用。