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Systematic functional study of 21st chromosome ortholog overexpression in C. elegans

线虫第 21 号染色体直系同源物过表达的系统功能研究

基本信息

批准号：
10651500
负责人：
JONATHAN THOMAS PIERCE
金额：
$ 6.62万
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：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651500
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease pathology Animal Model Apoptosis Behavioral Biological Assay Caenorhabditis elegans Characteristics Childhood Chromosome abnormality Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Code Consumption Defect Development Down Syndrome Early Onset Alzheimer Disease Epilepsy Essential Genes Etiology Frequencies GATA1 gene Gene Dosage Genes Genetic Health Human Individual Inherited Intellectual functioning disability Knock-in Lead Letters MAP Kinase Gene Methaqualone Modeling Molecular Mus Muscle Muscle function Mutate Natural regeneration Nematoda Nerve Degeneration Nervous system structure Neurons Orthologous Gene Pathway interactions Persons Phenotype Physiological Physiology Play Process Proteins RNA Interference Research Research Personnel Risk Role SYNJ1 gene Series Severities Sleep disturbances Speed Synapses Testing Time Transgenic Organisms axon guidance base behavioral study cholinergic cholinergic neuron congenital heart disorder cost dosage human stem cells improved in vivo in vivo Model induced pluripotent stem cell innovation insight knock-down leukemia motor disorder mouse model mutant neurobehavioral novel novel therapeutics overexpression partial trisomy 21 relating to nervous system screening stem cell model theories therapeutic target tool

项目摘要

PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability. For decades, we have known that an extra copy of the 21st chromosome (Hsa21) causes the broad array of physiological and developmental phenotypes associated with DS. However, we are far behind on addressing two critical questions in DS research: 1) Which Hsa21 genes cause phenotypes when overexpressed in DS, and conversely, 2) Which Hsa21 genes might be targeted to improve phenotypes in DS. Researchers using mouse models have discovered the role that a handful of Hsa21 genes play in certain phenotypes when overexpressed, such as Alzheimer’s pathology (APP) and leukemia (GATA1). The vast majority of Hsa21 genes, however, have not been studied in detail due to the impracticality of studying over 200 genes on Hsa21. Studying each of the Hsa21 genes using mouse models is time-consuming and costly. Instead, we propose to systematically study individual Hsa21 gene orthologs using the efficient model Caenorhabditis elegans. Recently, we found that, excluding 48 keratin genes, C. elegans has orthologs for over half of remaining Hsa21 genes, 51 of which are highly-conserved. Through mutant and RNAi analysis of the 51 orthologs, we found that 14 are essential genes and 10 are required for neural and/or muscular function, three of which had not previously been studied. To probe how overexpression (OE) of individual Hsa21 genes contributes to phenotypes relevant to DS, we will carry out complementary aims. For Aim 1, we will systematically test which of the 51 orthologs cause OE phenotypes one-by-one. For Aim 2, using a transgenic worm that carries extra copies of all 51 Hsa21 orthologs, we will systematically test which of the Hsa21 orthologs may be knocked down to reduce OE phenotypes. For OE phenotypes that we are able to suppress by gene knock down, we will also investigate the underlying cellular-molecular mechanistic bases with convenient approaches unique to C. elegans. Our project will leverage cutting-edge transgenic and gene knockdown tools, as well as take advantage of our lab’s expertise in high-throughput quantitative phenotyping. By identifying Hsa21 genes that cause phenotypes when overexpressed in C. elegans, this study will spotlight genes to prioritize for further study using 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 Hsa21 gene overexpression. Insights gained from this study will highlight novel and uncharacterized molecular pathways as potential therapeutic targets for improving health in those with DS.

项目概要/摘要唐氏综合症（DS）是智力障碍最常见的遗传原因。几十年来，我们已经知道第 21 号染色体 (Hsa21) 的额外拷贝会导致广泛的生理和与 DS 相关的发育表型。然而，我们在解决两个关键问题上还远远落后 DS 研究中的问题：1) 哪些 Hsa21 基因在 DS 中过度表达时会导致表型，以及相反，2) 哪些 Hsa21 基因可能被靶向改善 DS 的表型。研究人员使用鼠标模型发现了少数 Hsa21 基因在某些表型中发挥的作用过度表达，例如阿尔茨海默病病理学 (APP) 和白血病 (GATA1)。绝大多数 Hsa21 然而，由于研究 Hsa21 上的 200 多个基因是不切实际的，因此尚未对 Hsa21 基因进行详细研究。使用小鼠模型研究每个 Hsa21 基因既耗时又昂贵。相反，我们建议使用高效模型秀丽隐杆线虫系统地研究个体 Hsa21 基因直系同源物。最近，我们发现，排除 48 个角蛋白基因，线虫中超过一半的剩余 Hsa21 具有直系同源物基因，其中 51 个高度保守。通过对51个直向同源物的突变和RNAi分析，我们发现 14 个是必需基因，10 个是神经和/或肌肉功能所必需的，其中 3 个没有之前有研究过。探究单个 Hsa21 基因的过度表达 (OE) 如何促进与 DS 相关的表型，我们将实现互补的目标。对于目标 1，我们将系统地测试哪些 51 个直系同源物中的 51 个直系同源物一一导致 OE 表型。对于目标 2，使用携带额外所有 51 个 Hsa21 直向同源物的副本，我们将系统地测试哪些 Hsa21 直向同源物可能被敲除下调以减少 OE 表型。对于我们能够通过基因敲除来抑制的 OE 表型，我们将还通过独特的便捷方法研究潜在的细胞分子机制基础 C.线虫。我们的项目将利用尖端的转基因和基因敲除工具，并采取利用我们实验室在高通量定量表型分析方面的专业知识。通过鉴定 Hsa21 基因当在线虫中过度表达时会引起表型，这项研究将重点关注基因，以便进一步优先考虑使用小鼠和人类 DS 干细胞模型进行研究。生产的 Hsa21 OE 菌株集将被共享在世界各地自由建立线虫作为第一个方便研究的机制体内模型 Hsa21 基因过度表达的后果。从这项研究中获得的见解将突出新颖性和未表征的分子途径作为改善 DS 患者健康的潜在治疗靶点。