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

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点，精神分裂症是一种影响大约 1% 人口的衰弱性疾病。今年，神经生物学小组发表了描述涉及 NRG1-ErbB4 和 PI3K 酶 p110 的基因调控信号通路的数据，所有这些都与精神分裂症的风险相关。 Law 等人 (PNAS 2012) 表明，p110 的药理抑制可阻断安非他明对精神病小鼠模型的行为影响，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 已被证明可以增加治疗小鼠大脑中另一个 SZ 风险基因 AKT1 的磷酸化，这与其他抗精神病药物样分子一致，并表明其作用机制。 NRG1 和 ErbB4 已知对神经发育和大脑可塑性至关重要。我们实验室和其他实验室之前的报告表明，NRG1 的基因突变与 SZ 风险相关，同样，ErbB4 的基因变异和结构微缺失也会影响患病风险。虽然 NRG1 和 ErbB4 缺失小鼠表现出与其他 SZ 小鼠模型一致的行为模式，但人类死后 SZ 大脑也显示 NRG1 和 ErbB4 表达增加。这些基因的遗传变异会影响人类大脑的结构和功能，但这些变化如何导致疾病的机制仍不清楚。酶 p110 也与 SZ 相关，可以与下游的 NRG1/ErbB4 通路协同作用，并且已在对患者淋巴母细胞的研究中显示，其中酶水平有所增加。此外，在人类 SZ 大脑中，酶的表达有所增加。 NRG1 和 ErbB4 似乎可能是潜在的治疗靶点，但它们在细胞生理学中发挥作用，这使得它们不太可能成为靶点。更好的选择是，在 NRG1/ErbB4 下游起作用的 P110 可能被证明是可靶向的并提供最佳的治疗潜力。 遗传学和生物信息学核心实验室的研究人员继续鉴定新的 SZ 易感基因，并表征其在正常和患病状态下的作用机制。我们的临床、死后 DNA 和表型数据集经过整理，可使用基于网络的家庭传播和病例对照方法进行有效分析。遗传变异、基因型和统计遗传学结果与各个表型分析小组共享，包括临床神经心理学和神经影像核心实验室的研究人员、尸检部门和我们其他研究风险基因及其生物学影响的研究实验室的研究人员。我们根据文献、相互作用蛋白质网络的计算机搜索以及正在进行的合作的新发现来选择和优先考虑功能和位置候选基因。我们还继续对现有候选基因的变异进行鉴定和基因分型，并测试它们与 SZ、临床脑疾病分支的中间表型以及人类死后大脑、细胞和动物模型系统中的表达表型的关联。去年，Zhang 等人 (Biol Psych 2011) 在 4 个欧洲血统队列中对 ZNF804A（先前描述的 SZ 风险基因）中新发现的 SNP (rs7597593) 进行了关联研究。我们使用死后人脑测量了 SNP 对 mRNA 表达的影响。由于 GWAS 通常用于识别常见疾病的常见遗传变异，但在识别复杂疾病（如 SZ）的遗传变异方面不太成功，因此我们的研究提供了支持性证据，证明 rs7597593 与同样由女性驱动的 SZ 风险之间存在关联。在合并的 4 个样本和 US Gain 队列（所有样本中最大的样本）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 表达水平上发现了风险关联。在 4 个队列中的 3 个（德国、苏格兰和美国 GAIN）以及组合的 4 个病例对照队列样本中观察到关联和性别驱动的风险效应，但在 CBDB 美国队列中未观察到统计学显着性，其局限性不仅仅是可能的样本量。迄今为止，ZNF804A 基因的功能仍然未知。死后大脑中 mRNA 表达的结果和 ZNF804A 性别驱动的关联表明性别和 rs7597593 之间的风险分子机制。根据这项研究，我们无法将因果关系归因于这些遗传关联，因此对基因-基因相互作用的额外研究可能有助于揭示 ZNF804A 遗传变异影响疾病风险的机制。 另一个小组是我们的转基因小鼠和细胞模型实验室，它将人类基因突变转化为基因小鼠模型，作为研究精神分裂症发病机制、识别潜在药物靶点和测试抗精神病治疗新药的重要策略。在动物模型中捕获全部精神分裂症症状当然是不可能的，正如前面提到的，PNAS 文章啮齿动物模型已经成功地再现了几种类似精神分裂症的行为，并揭示了多巴胺和谷氨酰胺神经传递系统中特定基因的作用调解精神分裂症样行为。精神分裂症易感基因的发现以及将认知功能障碍作为该疾病的核心特征的发现，为开发和测试基于易感性的新型基因小鼠模型提供了机会。尽管基于遗传易感性的遗传小鼠模型相对较新，但我们仍在继续研究易感性基因在发育过程中大脑认知处理、神经元功能和信号转导中的作用。检查候选风险基因与环境因素的相互作用，很可能会让我们更好地了解精神分裂症病理生理学的分子机制，揭示正常认知功能和人脑发育的分子基础，并指导我们新的抗精神病疗法。最后，我们研究了 COMT 基因与精神分裂症的生物学和潜在治疗的关系。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 是一种精神分裂症风险基因，也是使多巴胺等儿茶酚失活和代谢的关键酶，在人类和动物模型的认知、唤醒、疼痛敏感性和应激反应性中发挥作用。 COMT 有两种形式：可溶性 (S) 和膜结合型 (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取向在细胞外空间中具有C末端催化结构域。 这表明 MB 能够使突触前和突触后神经元表面的突触和突触外多巴胺失活。我们还表明，COMT 抑制剂托卡朋通过细胞凋亡诱导细胞死亡，其细胞毒性呈剂量依赖性，并与人淋巴母细胞中的 COMT val/met 基因型相关。这些数据表明，可以开发出不渗透大脑细胞膜的抑制剂，并且对于那些表现出药物敏感性（COMT val/val 基因型）的抑制剂，在特定遗传背景下使用低剂量可能会减轻药物的毒性作用。

项目成果

RELN rs7341475 and schizophrenia risk: confusing, yet somehow intriguing.

• DOI: 10.1016/j.biopsych.2010.10.022
• 发表时间: 2011-03-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Tost, Heike;Weinberger, Daniel R.
• 通讯作者: Weinberger, Daniel R.

Early parental deprivation in the marmoset monkey produces long-term changes in hippocampal expression of genes involved in synaptic plasticity and implicated in mood disorder.

• DOI: 10.1038/npp.2008.106
• 发表时间: 2009-05
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Dysbindin and Schizophrenia: it's dopamine and glutamate all over again.

• DOI: 10.1016/j.biopsych.2010.10.028
• 发表时间: 2011-01-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Papaleo, Francesco;Weinberger, Daniel R.
• 通讯作者: Weinberger, Daniel R.

Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes.

• DOI: 10.1016/j.neubiorev.2009.06.005
• 发表时间: 2010-04
• 期刊: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
• 影响因子: 8.2
• 作者: Tost, Heike;Alam, Tajvar;Meyer-Lindenberg, Andreas
• 通讯作者: Meyer-Lindenberg, Andreas

Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans.

• DOI: 10.1523/jneurosci.4899-09.2010
• 发表时间: 2010-05-19
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Zink CF;Stein JL;Kempf L;Hakimi S;Meyer-Lindenberg A
• 通讯作者: Meyer-Lindenberg A