MOLECULAR AND GENETIC CORRELATES OF THE ONSET OF SCHIZOPHRENIA

精神分裂症发病的分子和遗传相关性

• 批准号: 7349609
• 负责人: TSUNG-UNG W. WOO
• 金额: $ 6.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349609
• 关键词: MOLECULAR; GENETIC; CORRELATES; ONSET; SCHIZOPHRENIA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schizophrenia (SCZ) is a devastating disease that disturbs the highest order of human brain functions. Many of its symptoms and deficits appear to be mediated by a large-scale prefrontal-limbic neural network (PLN), of which the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC), the hippocampus (HIPP), and the entorhinal cortex (EC) are key components. This neural system achieves functional maturation during late adolescence and early adulthood, which coincides with the typical age of onset of SCZ. Thus, the neurodevelopmental processes that mediate the maturation of the PLN may directly trigger or indirectly contribute to the onset of illness. At present, our understanding of the periadolescent development of the PLN is very limited. Thus, we will use high magnetic field structural, diffusion tensor, and magnetization transfer neuroimaging to systematically survey the course of periadolescent development of the gray matter and axonal connectivities within the monkey PLN, which is structurally and physiologically similar to its human counterpart. We will then utilize gene expression profiling combined with laser capture microdissection to uncover the genetic correlates of the periadolescent morphological changes of the DLPFC and the HIPP. We postulate that the pattern of gene expression will differ between the 2 regions, reflecing the synaptic reorganization process that is actively taking place during periadolescence in the former but not the latter region. Furthermore, it is hypothesized that the gene expression pattern will be similar between the white matter of the DLPFC and that of the EC, reflecting the concurrent myelination of axons that link subregions of the PLN. Finally, we will compare the periadolescent gene expression profiles of the monkey DLPFC with our existing human prefrontal microarray data obtained from SCZ and normal control subjects in order to identify genes that are differentially expressed both during periadolescent development and in SCZ. Quantitative real-time reverse transcriptase polymerase chain reaction will then be used to confirm these findings. Thus, this proposal seeks to characterize the morphometric maturation of the primate PLN, to define its genetic correlates, and, finally, to identify genes and molecular pathways that may be associated with the onset of SCZ. Ultimately, these data may inspire the conceptualization of novel intervention strategies that may be effective in attenuating or perhaps even preventing the onset of SCZ.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。精神分裂症（SCZ）是一种破坏性疾病，扰乱了人类大脑功能的最高秩序。其许多症状和缺陷似乎是由大规模的前额叶边缘神经网络（PLN）介导的，其中背外侧前额叶皮层（DLPFC）、前扣带皮层（ACC）、海马（HIPP）和内嗅皮层（EC）是关键组成部分。该神经系统在青春期晚期和成年早期实现功能成熟，这与SCZ的典型发病年龄相吻合。因此，介导PLN成熟的神经发育过程可能直接触发或间接促成疾病的发生。目前，我们对青春期周围PLN发育的了解非常有限。因此，我们将使用高磁场结构、扩散张量和磁化转移神经成像来系统地调查猴子PLN内灰质和轴突连接的青春期周围发育过程，猴子PLN在结构和生理上与人类相似。然后，我们将利用基因表达谱结合激光捕获显微解剖来揭示青春期周围DLPFC和HIPP形态变化的遗传相关性。我们假设这两个区域的基因表达模式会有所不同，这反映了突触重组过程在青春期前后活跃地发生在前一个区域而不是后一个区域。此外，假设DLPFC和EC的白质之间的基因表达模式相似，反映了连接PLN亚区域的轴突同时形成髓鞘。最后，我们将比较猴DLPFC的青春期周围基因表达谱与我们现有的从SCZ和正常对照中获得的人类前额叶微阵列数据，以确定青春期周围发育和SCZ中差异表达的基因。定量实时逆转录酶聚合酶链反应将被用来证实这些发现。因此，本研究旨在描述灵长类动物PLN的形态成熟特征，确定其遗传相关性，并最终确定可能与SCZ发病相关的基因和分子途径。最终，这些数据可能会启发新的干预策略的概念化，这些策略可能有效地减轻甚至预防SCZ的发生。