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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。精神分裂症（SCZ）是一种破坏性的疾病，会扰乱人类大脑的最高功能。它的许多症状和缺陷似乎是由大规模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）、海马体（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 的典型发病年龄一致。因此，介导 PLN 成熟的神经发育过程可能直接触发或间接导致疾病的发作。目前，我们对青春期 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研究猴子 PLN 内灰质和轴突连接的青春期发育过程，其在结构和生理上与人类对应物相似。然后，我们将利用基因表达谱与激光捕获显微切割相结合，揭示 DLPFC 和 HIPP 青春期形态变化的遗传相关性。我们假设这两个区域之间的基因表达模式会有所不同，反映了前一个区域在青春期期间活跃发生的突触重组过程，而后一个区域则不然。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 子区域的轴突同时发生髓鞘化。最后，我们将猴子 DLPFC 的青春期基因表达谱与我们现有的从 SCZ 和正常对照受试者获得的人类前额叶微阵列数据进行比较，以鉴定在青春期发育期间和 SCZ 中差异表达的基因。然后将使用定量实时逆转录酶聚合酶链反应来证实这些发现。因此，该提案旨在表征灵长类 PLN 的形态成熟，定义其遗传相关性，最后确定可能与 SCZ 发病相关的基因和分子途径。最终，这些数据可能会激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。