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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要唐氏综合症（DS）是智力残疾的最常见遗传原因。而社会改进已经提高了DS患者的生活质量，该染色体（HSA21）基因负责容纳DS的众多特征表型仍然未知。这些包括智力残疾，运动不协调，肌肉张力低下和颅面异常，在整个环境中保持一致患有DS的人以及其他可变的合并症，例如先天性心脏病和自闭症，仅举几例。尽管鼠标模型阐明了某些HSA21基因在某些表型，例如阿尔茨海默氏病（APP）和白血病（GATA1），大多数HSA21基因都没有被详细研究。这项研究将规避鼠标模型的耗时和昂贵的用法通过系统地研究哪些HSA21基因引起行为缺陷来研究单个HSA21基因当在有效的秀丽隐杆线虫中过表达时。我们的实验室发现秀丽隐杆线索共享51 与人类21染色体的高度保存基因。通过研究这些基因的突变体，我们发现在蠕虫中，14 HSA21直系同源物是必不可少的基因，神经或肌肉功能，其中3个以前没有研究过。这项研究将使用上位分析来进一步在功能上表征了那些新型基因MTQ-2之一，它似乎是重要的新颖修饰符突触G蛋白信号传导。此外，探测单个HSA21基因的过表达（OE）有助于DS表型，一组51 C.秀丽隐杆线虫转基因菌株过表达不同将生成保守的HSA21直系同源物。该集将使用高通量来评估该集合定量行为分析以推断出哪些基因引起神经或肌肉功能障碍时过表达。这项研究将通过得克萨斯大学高度支持和资源良好的神经科学研究生课程，在有足够的PI的指导下体验心理成功的博士生。实习生通过建立一个大型女性STEM专业组织。受到DS姐姐的启发，学员计划申请她在博士后培训后，领导，科学专业知识和个人见解可以运行DS实验室。经过识别在秀丽隐杆线虫过表达时引起表型的HSA21基因，该研究将聚焦基因优先考虑她和其他人在小鼠和人类干细胞模型中的进一步研究。集合产生的HSA21 OE菌株将在世界各地自由共享，以建立秀丽隐杆线虫作为第一个机械体内模型，可方便地研究单个HSA21基因OE的后果。这将促进 DS通过其他蠕虫实验室进行的研究，并允许其他DS实验室扩展其模型系统的曲目研究特定的HSA21基因。从这项研究中获得的见解将突出基因和途径为潜力改善DS患者健康的治疗靶标。