BRAIN VENTRICLE DEVELOPMENT AND MENTAL HEALTH

描述(申请人提供)：脑室是一个高度保守的含有脑脊液的腔系统，被认为可以保护大脑免受损伤，清除废物，并携带化学信号。自由液体循环受阻会导致脑积水，这是最常见的出生缺陷之一。此外，在精神分裂症和自闭症患者中，脑室结构和大小的异常已被广泛记录在案。这一探索性的建议试图以斑马鱼为模型，并以一组脑室突变的定义作为研究的基础，试图了解脑室形成的遗传基础。更长期的目标是了解与这些突变相对应的基因在脑室系统形成中所起的作用，并解决它们的功能障碍是否导致自闭症、精神分裂症和相关疾病的病因。斑马鱼已被证明是研究包括大脑形成和功能在内的发育生物学问题的极好的遗传和分子模型，并已成为许多人类疾病的模型。它假设脑室的形态和功能可能改变脑功能，反过来，脑室的形成和维持依赖于正常的脑功能。在初步研究中，描述了斑马鱼脑室形成的时间过程，并检测了3个脑室发育缺陷的突变体。首先，建议通过分析(I)相对于野生型鱼类胚胎的分子和细胞生物学变化，(Ii)它们功能的细胞自主性，以及(Iii)它们之间的上位相互作用(功能层次)，来继续对这些突变体进行表征。其次，来自化学诱变筛选的28个已报告具有脑室表型但其他未被研究的突变体将被进一步分析。将与麻省理工学院南希·霍普金斯博士合作，通过筛选275个已确定候选基因的逆转录病毒插入突变体来定义更多的突变体。脑室突变将被归类为克隆相应基因的前奏。这项研究将确定正常脑室形成所需的大量基因，这些基因可能显示精神健康障碍患者的异常活动。

DESCRIPTION (provided by applicant): Brain ventricles are a highly conserved system of cavities that contain cerebrospinal fluid and are believed to protect the brain from injury, remove waste, and carry chemical signals. Blockage of free fluid circulation leads to hydrocephalus, one of the most common birth defects. Additionally, abnormalities in brain ventricle structure and size have been extensively documented in individuals affected with schizophrenia and autism. This exploratory proposal seeks to understand the genetic basis for brain ventricle formation, using the zebrafish as a model, and definition of a set of brain ventricle mutants as the foundation for the study. The longer term goal is to understand the role that genes corresponding to these mutants play in formation of the brain ventricular system, and to address whether their misfunction contributes to the etiology of autism, schizophrenia and related disorders. The zebrafish has proven an excellent genetic and molecular model for issues in developmental biology including brain formation and function, and has served as a model for many human diseases. It is hypothesized that ventricle morphology and function may alter brain function, and conversely, that ventricle formation and maintenance is dependent on normal brain function. In preliminary studies, the timecourse of brain ventricle formation in the zebrafish has been described and 3 mutants with defects in brain ventricle development have been examined. It is proposed, firstly, to continue characterization of these mutants by analyzing (i) molecular and cell biological changes relative to wild type fish embryos, (ii) cell autonomy of their function and (iii) epistatic interactions between them (hierarchy of function). Secondly, 28 mutants reported to have brain ventricle phenotypes, but otherwise unstudied, that were derived from chemical mutagenesis screens will be further analyzed. Additional mutants will be defined in collaboration with Dr. Nancy Hopkins, MIT, by screening through 275 retroviral insertional mutants for which candidate genes have been identified. Brain ventricle mutants will be categorized as a prelude to cloning corresponding genes. This study will define a large collection of genes required for normal brain ventricle formation, and which may display abnormal activity in patients with mental health disorders.