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: 10315961
• 负责人: Sophia M Sanchez
• 金额: $ 3.66万
• 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/10315961
• 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; 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; Phenotype; Physiological; Play; Presenile Alzheimer Dementia; 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.

项目摘要 唐氏综合征（DS）是智力残疾最常见的遗传原因。虽然社会进步 提高了DS患者的生活质量，其中21号染色体（Hsa 21）基因负责 伴随DS的大量特征性表型仍然未知。其中包括知识分子 残疾，运动不协调，低肌张力和颅面异常，这些都是一致的， 患有DS的人，以及其他可变发生的并发症，如先天性心脏病和 孤独症，仅举几例。尽管小鼠模型揭示了一些Hsa 21基因在 在某些表型，如阿尔茨海默病（APP）和白血病（GATA 1），大多数Hsa 21基因没有 被详细研究过。这项研究将避免耗时和昂贵的小鼠模型的使用， 通过系统研究哪些Hsa 21基因导致行为缺陷来研究单个Hsa 21基因 当在高效模型秀丽隐杆线虫中过表达时。我们的实验室发现C. elegans shares 51 与人类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， 发现在蠕虫中，14个Hsa 21直系同源物是必需基因，10个Hsa 21直系同源物是神经或 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进一步 功能特征的新基因之一，mtq-2，这似乎是一个重要的新的修饰剂， 突触G蛋白信号此外，为了探索单个Hsa 21基因的过表达（OE）如何 有助于DS表型，一组51 C。每种转基因菌株都过表达一种不同的 将产生保守的Hsa 21直系同源物。将使用高通量， 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PI的指导下， 指导成功的博士生。这位受训者通过建立一个大型的 妇女STEM专业组织。受一位患有DS的姐妹的启发，这位学员计划将她应用于 领导力，科学专业知识和个人见解，在博士后培训后运行DS实验室。通过 鉴定当在C. elegans这项研究将聚焦于 她和其他人在小鼠和人类DS干细胞模型中优先进行进一步的研究。该组 生产的Hsa 21 OE菌株将在世界范围内免费共享，以建立C.作为第一个 这是一种体内机制模型，可以方便地研究单个Hsa 21基因OE的后果。 DS研究由其他蠕虫实验室进行，并允许其他DS实验室扩展他们的模型系统库， 研究特定的Hsa 21基因从这项研究中获得的见解将突出基因和途径作为潜在的 改善DS患者健康的治疗目标。