Systematic Analysis of 21st Chromosome Ortholog Overexpression in C. elegans

线虫 21 号染色体直向同源物过度表达的系统分析

• 批准号: 10488058
• 负责人: Sophia M Sanchez
• 金额: $ 4.37万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488058
• 关键词: Abnormal coordination; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Animals; Behavior; Behavioral; Behavioral Assay; Biochemical; Biological Models; Brain; Caenorhabditis elegans; Characteristics; Childhood; Chromosome abnormality; Chromosomes; Code; Complement; Consumption; Craniofacial Abnormalities; Defect; Development; Down Syndrome; Early Onset Alzheimer Disease; Epilepsy; Essential Genes; Etiology; Foundations; Frequencies; Functional disorder; GATA1 gene; GTP-Binding Proteins; Gene Dosage; Gene Targeting; Genes; Genetic; Genetic Epistasis; Genetic Models; Genetic Transcription; Health; Human; Individual; Institutes; Intellectual functioning disability; Lead; Leadership; Light; Mentors; Methaqualone; Modeling; Motor; Mus; Muscle; Muscle Tonus; Muscle function; Mutate; Names; Nematoda; Nerve Degeneration; Nervous system structure; Neurons; Neurosciences; Orthologous Gene; Pathway interactions; Penetrance; Persons; Phenotype; Physiological; Play; Professional Organizations; Protein Methyltransferases; Proteins; Quality of life; Reporter; Reporting; Research; Resources; Risk; Role; Running; SYNJ1 gene; Series; Severities; Signal Transduction; Signaling Protein; Sister; Sleep disturbances; Speed; Study models; Synapses; Testing; Texas; Time; Transgenic Organisms; Universities; Woman; Yeasts; autism spectrum disorder; behavioral study; cholinergic; comorbidity; congenital heart disorder; cost; cost effective; doctoral student; dosage; experience; human stem cells; improved; in vivo; in vivo Model; insight; leukemia; motor disorder; mouse model; mutant; novel; overexpression; partial trisomy 21; post-doctoral training; programs; relating to nervous system; stem cell model; synaptic function; theories; therapeutic target

PROJECT SUMMARY Down syndrome (DS) is the most common genetic cause of intellectual disability. While societal improvements have enhanced the quality of life for those with DS, which 21st chromosome (Hsa21) genes are responsible for the multitude of characteristic phenotypes that accompany DS remains unknown. These include intellectual disability, motor incoordination, low muscle tone, and craniofacial abnormalities, which are consistent across people with DS, as well as other variably-occurring co-morbid conditions such as congenital heart disease and autism, to name just a few. Although mouse models have shed light on the role some Hsa21 genes play in some phenotypes, such as Alzheimer’s pathology (APP) and leukemia (GATA1), most Hsa21 genes have not been studied in detail. This study will circumvent the time-consuming and costly use of mouse models for the study of individual Hsa21 genes by systematically investigating which Hsa21 genes cause behavioral deficits when overexpressed in the efficient model Caenorhabditis elegans. Our lab found that C. elegans shares 51 highly-conserved genes with the human 21st chromosome. Through the study of mutants for these genes, we found that in worm 14 Hsa21 orthologs are essential genes and 10 Hsa21 orthologs are required for neural or muscular function, 3 of which had not previously been studied. This study will use epistasis analysis to further functionally characterize one of those novel genes, mtq-2, which appears to be an important novel modifier of synaptic G-protein signaling. Additionally, to probe how overexpression (OE) of individual Hsa21 genes contributes to DS phenotypes, a set of 51 C. elegans transgenic strains that each overexpresses a different conserved Hsa21 ortholog will be generated. This set will be assessed one-by-one using high-throughput, quantitative behavioral analyses to deduce which genes cause neural or muscular dysfunction when overexpressed. This research will be conducted through the University of Texas’s highly supportive and well-resourced Institute for Neuroscience graduate program, under the direction of a PI who has ample experience mentoring successful PhD students. The trainee has demonstrated leadership by founding a large women’s STEM professional organization. Inspired by a sister with DS, the trainee plans to apply her leadership, scientific expertise, and personal insights to run a DS lab following postdoctoral training. By identifying Hsa21 genes that cause phenotypes when overexpressed in C. elegans, this study will spotlight genes to prioritize for further study by her and others in mouse and human stem-cell models of DS. The set of Hsa21 OE strains produced will be shared freely around the world to establish C. elegans as the first mechanistic in vivo model to conveniently study consequences of individual Hsa21 gene OE. This will promote DS research by additional worm labs and allow other DS labs to expand their repertoire of model systems for studying specific Hsa21 genes. Insights gained from this study will highlight genes and pathways as potential therapeutic targets for improving health in those with DS.

项目总结 唐氏综合症(DS)是导致智力残疾的最常见的遗传原因。在社会进步的同时 提高了DS患者的生活质量，这与21号染色体(Hsa21)基因有关 伴随DS的多种特征表型尚不清楚。这些人包括知识分子 残疾、运动不协调、肌肉张力低下和头面部异常，这些都是一致的 患有DS的人，以及其他不同的并存疾病，如先天性心脏病和 自闭症，仅举几例。尽管小鼠模型已经阐明了一些Hsa21基因在 一些表型，如阿尔茨海默病(APP)和白血病(GATA1)，大多数Hsa21基因没有 已经进行了详细的研究。这项研究将避免使用耗时且昂贵的小鼠模型 通过系统研究哪些Hsa21基因导致行为缺陷来研究单个Hsa21基因 当在高效的秀丽线虫模型中过度表达时。我们的实验室发现，线虫分享了51 人类21号染色体高度保守的基因。通过对这些基因突变的研究，我们 发现在蠕虫中，14个Hsa21同源基因是必需的基因，而10个Hsa21同源基因是神经或 肌肉功能，其中3个以前没有研究过。本研究将使用上位性分析来进一步 对其中一个新基因MTQ-2进行了功能表征，它似乎是一种重要的新修饰物 突触G蛋白信号。此外，为了探讨单个Hsa21基因的过度表达(OE) 与DS表型有关，这是一组51个线虫转基因菌株，每个都过度表达不同的 将生成保守的HSA21直射同源数据。将使用高吞吐量逐个评估该集合， 定量行为分析，以推断哪些基因导致神经或肌肉功能障碍 过度表达。这项研究将通过德克萨斯大学的高度支持和 资源充足的神经科学研究所研究生课程，在拥有充足资金的PI的指导下 指导成功的博士生的经验。实习生通过创建一家大型企业展示了领导力 女子STEM专业组织。受DS患者姐姐的启发，这位实习生计划将她 领导力、科学专业知识和个人洞察力，以在博士后培训后运营DS实验室。通过 确定线虫过表达时导致表型的Hsa21基因，这项研究将成为焦点 她和其他人在DS的小鼠和人类干细胞模型中优先研究的基因。这一组 生产的HSA21 OE菌株将在世界各地自由共享，以建立第一个线虫 体内机制模型，便于研究单个Hsa21基因OE的后果。这将促进 由更多的WORM实验室进行DS研究，并允许其他DS实验室扩展其模型系统库 研究特定的Hsa21基因。从这项研究中获得的见解将突出基因和通路的潜力 改善DS患者健康的治疗目标。