Brain Ventricle Development and Mental Health

脑室发育与心理健康

• 批准号: 7087856
• 负责人: Laura Anne LOWERY
• 金额: $ 4.48万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2008-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087856
• 关键词: biological models; cerebral ventricles; developmental neurobiology; neurogenetics; nonmammalian vertebrate embryology; predoctoral investigator; sodium potassium exchanging ATPase; zebrafish

DESCRIPTION (provided by applicant): This proposal is designed to study the mechanisms underlying initial brain ventricle inflation, using a genetic approach in zebrafish. The brain ventricles are a conserved system of cavities containing cerebrospinal fluid that are required for normal brain function. Abnormalities in brain ventricle structure can lead to hydrocephaly and are correlated with many mental health disorders including autism and schizophrenia. The molecular mechanisms underlying brain ventricle development are poorly understood. The zebrafish is an excellent model for this study, as the brain ventricles are visible throughout development, and many genetic, molecular, and embryological tools are available. Research in the Sive laboratory has demonstrated that brain ventricle formation is a multi-step process, involving at least two steps: formation and maintenance of epithelial integrity by junction-associated proteins, and initial inflation of the ventricles with fluid, which requires the snk (atp1a1a.1) gene encoding a Na K ATPase. This proposal will test the hypothesis that the Snk protein functions in initial brain ventricle inflation by acting locally. Tissue transplants and mosaic analysis will be used to ask whether limited wild-type Atp1a1a.1 function can rescue snk mutants. Additionally, this proposal will test the hypothesis that multiple genes synergize with Snk to direct initial brain ventricle inflation. Five mutants isolated from chemical screens and two from an insertion mutagenesis screen show a putative brain inflation phenotype. These will be tested for synergistic effects with the Snk protein. This analysis will exploit the zebrafish to determine the mechanisms underlying brain ventricle inflation and that are required to build normal brain structure, which may be perturbed in mental health disorders.

描述（由申请人提供）：该提案旨在使用斑马鱼中的遗传方法研究初始脑心室通胀的基础机制。 脑室是一种含有正常脑功能所需的脑脊液的腔体系统。 脑心室结构的异常会导致脑畸形，并与许多心理健康疾病有关，包括自闭症和精神分裂症。 脑心室发育的分子机制知之甚少。 斑马鱼是这项研究的绝佳模型，因为在整个发育过程中都可以看到脑室，并且许多遗传，分子和胚胎学工具都可以使用。 SIVE实验室的研究表明，脑心室形成是一个多步骤过程，涉及至少两个步骤：通过接线相关的蛋白质形成和维持上皮完整性，以及与液体中心的初始通胀，需要SNK（ATP1A1A.1）基因编码NA KATPase。该提案将检验以下假设：SNK蛋白通过局部作用在初始脑室通胀中起作用。 组织移植和镶嵌分析将用于询问有限的野生型ATP1A1A.1功能是否可以挽救SNK突变体。 此外，该提案将检验以下假设：多个基因与SNK协同以指导初始脑室通胀。 从化学筛选中分离出来的五个突变体和两个从插入诱变筛选中显示出假定的脑通胀表型。 这些将通过SNK蛋白进行协同作用测试。 该分析将利用斑马鱼来确定脑心室通胀的基础机制，并建立正常的大脑结构所需的机制，这可能会在精神健康障碍中受到干扰。