Identification of bacterial products required for brain development

鉴定大脑发育所需的细菌产物

基本信息

批准号：
9807763
负责人：
JUDITH S EISEN
金额：
$ 22.13万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807763
关键词：
Ablation Affect Alzheimer&apos s Disease Animals Anxiety Bacteria Bacterial Proteins Behavior Behavioral Biochemical Bioinformatics Biological Assay Brain Brain region Development Diagnostic Disease Failure Gene Expression Genetic Germ-Free Gnotobiotic Homologous Gene Human Impairment Individual Interneurons Intestines Investigation Knowledge Larva Lead Learning Link Mental Depression Modeling Molecular Morphology Motor Activity Nature Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Outcome Parkinson Disease Phenocopy Phenotype Play Population Process Protein Analysis Reporting Research Role Schizophrenia Surface Testing Therapeutic Visual system structure Work Zebrafish autism spectrum disorder bacterial community bacterial genetics base developmental disease dysbiosis gut microbiota insight member microbiome microbiota mouse model nervous system development neurodevelopment neuronal circuitry normal microbiota novel offspring preference social superior colliculus Corpora quadrigemina targeted treatment vision development

项目摘要

There is mounting evidence that the intestinal microbiota play an important role in normal nervous system development, although the underlying molecular mechanisms are generally unknown. We propose to investigate the role of the intestinal microbiota in development of an identified population of superficial interneurons (SINs) in the zebrafish optic tectum that are required for visually-guided prey capture behavior. Previous work showed that prey capture is significantly impaired in larvae in which SINs are genetically ablated. We find that the microbiota are necessary for SINs to differentiate their GABAergic phenotype, and consequently larvae reared germ free (GF), in the absence of bacteria, phenocopy the prey capture deficit of larvae in which SINs have been ablated. We hypothesize that members of the zebrafish-associated microbiota normally produce molecular products that promote SIN differentiation. We will test this hypothesis using an unbiased screen to identify bacterial products that affect SIN differentiation. First we will use gnotobiotic zebrafish colonized with specific zebrafish bacterial isolates to learn which bacterial species are required for normal SIN development and prey capture behavior. We will then take advantage of a pipeline we established that utilizes bacterial genetics, bioinformatics, and biochemical approaches, to learn the molecular nature of the bacterial products. Discovering the molecular mechanisms by which host-associated bacteria promote normal nervous system development will provide important new insights into a fundamental process that is not well understood, reveal how this process can go awry during intestinal dysbiosis, an imbalance that has been linked to neurodevelopmental conditions such as autism spectrum disorder and schizophrenia, and provide new possibilities for developing targeted therapies.

有越来越多的证据表明肠道菌群在正常神经系统中起重要作用发展，尽管基本的分子机制通常是未知的。我们建议研究肠道菌群在确定浅表群体的发展中的作用视觉引导的猎物捕获行为所需的斑马鱼视力膜中的中间神经元（罪）。先前的工作表明，猎物捕获在罪恶上是遗传上的幼虫中受到的显着损害消融。我们发现，微生物群是犯罪区分其GABA能表型所必需的，并且因此，在没有细菌的情况下，幼虫饲养了胚芽（GF），捕食捕获不足杀害罪的幼虫。我们假设斑马鱼相关的微生物群的成员通常产生促进罪分化的分子产物。我们将使用公正的屏幕以识别影响罪分化的细菌产物。首先，我们将使用gnotobiotic 斑马鱼用特定的斑马鱼细菌分离株殖民，以了解需要哪种细菌物种正常的罪恶发展和猎物捕获行为。然后，我们将利用建立的管道利用细菌遗传学，生物信息学和生化方法来学习细菌产物。发现与宿主相关细菌促进的分子机制正常的神经系统发展将为不是一个基本过程提供重要的新见解良好的理解，揭示了在肠道营养不良期间该过程如何出现的，这是一种失衡与自闭症谱系障碍和精神分裂症等神经发育状况有关，并提供开发目标疗法的新可能性。