DISC1-dependent defects in neural fate, corticogenesis and cognition in psychosis

精神病中神经命运、皮质生成和认知的 DISC1 依赖性缺陷

• 批准号: 8801088
• 负责人: Koko Ishizuka
• 金额: $ 63.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8801088
• 关键词: Address; Alzheimer' s Disease; Animals; Anterior; Architecture; Area; Auditory area; Behavior; Behavioral; Behavioral Sciences; Biological; Biological Markers; Biopsy; Bipolar Disorder; Brain; Brain imaging; Brain region; Categories; Cells; Cellular biology; Characteristics; Chromosomal translocation; Clinical; Cognition; Cognitive; Data; Defect; Development; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Dimensions; Disease; Event-Related Potentials; Genes; Genetic; Grant; Human; Image; Impairment; In Vitro; Individual; Inherited; Link; Magnetic Resonance Imaging; Maintenance; Major Depressive Disorder; Major Mental Illness; Measures; Mediating; Mental disorders; Molecular; Molecular Abnormality; Molecular Profiling; National Institute of Mental Health; Neurobiology; Neurocognitive; Neurons; Neurosciences; Open Reading Frames; Outpatients; Participant; Pathology; Phenotype; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Prefrontal Cortex; Psychopathology; Psychotic Disorders; Publishing; Research; Research Domain Criteria; Research Infrastructure; Role; Schizophrenia; Science; Serine; Short-Term Memory; Study Section; Surface; System; Thick; Tissues; Transcript; Translational Research; Translations; Uncertainty; Update; base; cingulate cortex; clinical application; flexibility; genetic pedigree; genetic variant; genome wide association study; induced pluripotent stem cell; interest; migration; neural circuit; neurodevelopment; neuropsychological; progenitor; public health relevance; reconstruction; relating to nervous system; research study; tau phosphorylation; trait

DESCRIPTION (provided by applicant): The diagnostic boundaries defined by current diagnostic systems (e.g., DSM) are now being challenged by recent advances in the genetic architecture underlying psychiatric disorders. Meanwhile, NIMH has launched the Research Domain Criteria project (RDoC) to develop, for research purposes, new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures beyond the current diagnostic systems. The DISC1 gene was originally discovered as the sole disrupted transcript with an open reading frame, at the breakpoint of an inherited chromosomal translocation in a Scottish pedigree: it segregates with a variety of major mental illnesses, including schizophrenia (SZ), bipolar disorder (BP), and major depression. Nonetheless, genome wide association studies have failed to detect associations between DISC1 locus and SZ (or other DSM-categorized diseases thus far). In contrast, the data from association studies of DISC1 with anatomical, physiological, and behavioral traits, which commonly underlie the pathology of major mental illnesses, have been promising. Thus, we hypothesize that DISC1 is a promising target to address mechanisms underlying mental illnesses across diagnostic categories in the RDoC framework: DISC1 may be a good probe that mediates translation from the discoveries in basic genetics, neuroscience, and behavioral science into clinical application. Based on our preliminary data, we further hypothesize that a decrease in the level of phosphorylation at serine-713 of human DISC1 (pS713-DISC1) underlies delayed neural differentiation, which disturbs neural circuitry formation in the brain development and, in turn, interferes with the acquisition of working memory. We will study relatively stable outpatients with SZ and BP, as well as well-matched healthy controls. Within the RDoC framework, our construct of interest is working memory (cognitive domain), whereas the independent variable is pS713-DISC1 (molecule). Our dependent variables include neuronal fate (cells), cortical surface area, thickness, and volume (circuit), and working memory (behavior). Johns Hopkins Schizophrenia Center has established an infrastructure of translational research in which we conduct clinical/neuropsychological assessment, brain imaging, and multiple tissue biopsies for molecular and cellular study simultaneously from each study participant. This infrastructure allows us to perform experiments in which molecular, anatomical, and behavioral data will be obtained from the same individuals. By utilizing this potential strength, we will address how behavior and neuroanatomical abnormalities relevant to psychotic disorders (SZ and BP currently categorized by DSM) are quantitatively associated with a specific molecular signature (phosphorylation of DISC1 in this study).

描述（由申请人提供）：由当前诊断系统定义的诊断边界（例如，DSM）现在正受到精神疾病遗传结构的最新进展的挑战。与此同时，NIMH已经启动了研究领域标准项目（RDoC），以研究为目的，基于可观察行为和超越当前诊断系统的神经生物学测量的维度，开发对精神病理学进行分类的新方法。 DISC 1基因最初被发现是唯一一个被破坏的转录本，具有开放的阅读框架，位于苏格兰血统中遗传性染色体易位的断点处：它与各种主要精神疾病分离，包括精神分裂症（SZ），双相情感障碍（BP）和重度抑郁症。尽管如此，全基因组关联研究未能检测到DISC 1基因座与SZ（或迄今为止的其他DSM分类疾病）之间的关联。相比之下，DISC 1与解剖学、生理学和行为学特征的关联研究数据（这些特征通常是主要精神疾病病理学的基础）一直很有希望。因此，我们假设DISC 1是一个很有前途的目标，以解决RDoC框架中诊断类别的精神疾病的潜在机制：DISC 1可能是一个很好的探针，介导从基础遗传学，神经科学和行为科学的发现转化为临床应用。 基于我们的初步数据，我们进一步假设人DISC 1（pS 713-DISC 1）丝氨酸-713磷酸化水平的降低是神经分化延迟的基础，这干扰了大脑发育中的神经回路形成，进而干扰了工作记忆的获得。我们将研究相对稳定的门诊患者， SZ和BP，以及匹配良好的健康对照。在RDoC框架内，我们感兴趣的结构是工作记忆（认知域），而自变量是pS 713-DISC 1（分子）。我们的因变量包括神经元命运（细胞），皮质表面积，厚度和体积（电路），以及工作记忆（行为）。 约翰霍普金斯精神分裂症中心已经建立了转化研究的基础设施，我们对每个研究参与者同时进行临床/神经心理学评估、脑成像和多个组织活检，以进行分子和细胞研究。这种基础设施使我们能够进行实验，其中分子，解剖学和行为数据将从相同的个体获得。通过利用这种潜在的力量，我们将解决如何行为和神经解剖异常相关的精神障碍（SZ和BP目前分类的DSM）是定量相关的特定分子签名（磷酸化DISC 1在这项研究中）。