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Characterization of a Novel Ataxia Phenotype

新型共济失调表型的表征

基本信息

批准号：
10602557
负责人：
Alexander Telenson
金额：
$ 4.36万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2021-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602557
关键词：
Affect Alleles Animal Model Animal Sources Ataxia Backcrossings Bioinformatics Biological Process Brain Stem Breeding Candidate Disease Gene Cells Central Nervous System Cerebellum Cessation of life Chromosome Mapping Computer Analysis Critical Pathways Data Defect Development Disease Embryonic Development Ensure Equilibrium Essential Genes Exclusion Fluorescent in Situ Hybridization Gene Expression Generations Genes Genetic Genetic Complementation Test Genetic Variation Genome Genotype Goals Growth Heterozygote Human Inherited Light Longevity Missense Mutation Modeling Molecular Mus Mutant Strains Mice Mutation Neurologic Nonsense Mutation Nutritional Pathology Pattern Phenotype Principal Investigator Probability Process Severities Slice Spinal Ganglia Stains Time Tissues Training Untranslated RNA Validation Variant autosome causal variant cell type design differential expression experimental study genetic approach genetic variant genome analysis genome sequencing human disease insight mouse model mutant neurodevelopment neuromuscular neuropathology novel postnatal postnatal development postnatal period segregation skills success therapeutic development transcriptome sequencing transcriptomics whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Defining genetic variation responsible for neuromuscular phenotypes has provide insight about basic neurological mechanisms as well as insight on human disease mechanisms. Mouse models have also been used to understand genetic mechanisms that cause relevant neurological conditions. These discoveries were made through the classic genetic approach of characterizing a phenotype and then defining the genotype that accounts for that defect. This approach has been instrumental for a host of discoveries resulting in a more thorough understanding of underlying mechanisms of disease. The project put forth under this proposal follows a similar approach. We seek to identify and characterize a potentially novel variant responsible for a severe, “novel ataxia phenotype” (nap) discovered in our lab with the ultimate goal of shedding light on novel mechanisms underlying ataxia. This proposal outlines experiments to characterize the affected tissue type and evaluate whole genome sequencing (WGS) and RNA sequencing to isolate potentially causal genetic variants to experimentally validate. This approach ensures that progress is not wholly dependent on a specific result, rather several experiments can be done in concert that will increase the probability of success. Our approach of utilizing WGS will providing the genetic landscape thereby elucidating potential noncoding variants that may elicit the phenotype in the nap mice. After determining which tissue type is affected, we will perform RNA sequencing to elucidate transcriptomic differences in the nap mice to provide potential mechanisms underlying the phenotype. Successfully identifying the variant through computationally analysis and experimental validation will allow for further experiments to better understand the mechanism of action of the variant, as outlined in the aims. Given the presentation of the ataxia phenotype, we suspect the primary tissue affected will be the cerebellum and/or brainstem and through breeding, we have established that this variant is inherited in an autosomal recessive pattern. Through preliminary genome analysis, we have identified several novel candidates and excluded several known genes responsible for ataxia phenotypes. The results of this project are expected to provide further insight into the molecular mechanisms that underlie ataxia and will potentially serve as a model for therapeutic development to ameliorate ataxia symptomology. This project was designed to expand the skills and training of the principal investigator with the goal of comprehensive training in bioinformatics and characterization of the mouse model.

项目总结/文摘