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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.

项目总结/文摘