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.

项目概要 唐氏综合症（DS）是智力障碍最常见的遗传原因。在社会进步的同时 提高了 DS 患者的生活质量，21 号染色体 (Hsa21) 基因负责 DS 伴随的众多特征表型仍然未知。这些包括知识分子 残疾、运动不协调、肌张力低和颅面异常，这些在不同人群中都是一致的 患有 DS 的人，以及其他易发生的共病疾病，例如先天性心脏病和 自闭症，仅举几例。尽管小鼠模型已经揭示了一些 Hsa21 基因在 一些表型，例如阿尔茨海默病病理（APP）和白血病（GATA1），大多数 Hsa21 基因没有 进行了详细研究。这项研究将避免使用小鼠模型进行耗时且昂贵的研究 通过系统地调查哪些 Hsa21 基因导致行为缺陷来研究个体 Hsa21 基因 当在高效模型秀丽隐杆线虫中过度表达时。我们的实验室发现线虫共有 51 个 人类第21号染色体高度保守的基因。通过对这些基因突变体的研究，我们 发现在线虫中 14 个 Hsa21 直向同源物是必需基因，并且 10 个 Hsa21 直向同源物是神经或 肌肉功能，其中 3 种以前未曾研究过。本研究将使用上位分析来进一步 对其中一个新基因 mtq-2 进行功能表征，它似乎是一个重要的新修饰因子 突触 G 蛋白信号传导。此外，探究单个 Hsa21 基因的过度表达 (OE) 有助于 DS 表型，一组 51 个秀丽隐杆线虫转基因菌株，每个菌株过表达不同的 将生成保守的 Hsa21 直系同源物。该集合将使用高通量进行逐一评估， 定量行为分析，以推断哪些基因会导致神经或肌肉功能障碍 过度表达。这项研究将在德克萨斯大学的大力支持下进行 资源丰富的神经科学研究所研究生项目，在拥有充足资源的 PI 的指导下 指导成功博士生的经验。该实习生通过创办一家大型公司展现了领导才能 女性 STEM 专业组织。受到一位患有 DS 的姐妹的启发，实习生计划将她应用到 在博士后培训后运营 DS 实验室的领导力、科学专业知识和个人见解。经过 这项研究确定了在线虫中过度表达时导致表型的 Hsa21 基因，该研究将重点关注 她和其他人在 DS 小鼠和人类干细胞模型中优先研究的基因。的集合 生产的 Hsa21 OE 菌株将在世界范围内自由共享，使线虫成为第一个 机制体内模型，可方便地研究单个 Hsa21 基因 OE 的后果。这将促进 由其他蠕虫实验室进行 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途径的潜力 改善 DS 患者健康的治疗目标。