Developing a murine TPI Df model

开发小鼠 TPI Df 模型

基本信息

批准号：
10294798
负责人：
Michael John Palladino
金额：
$ 15.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2021-08-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294798
关键词：
Affect Amino Acid Substitution Anemia Animal Testing Animals Behavior Behavior assessment Behavioral Behavioral Assay Biochemical Biological Assay Brain Injuries Breeding Cessation of life Childhood Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Communities Defect Deletion Mutation Development Diagnosis Disease Enzymes Escherichia coli Exhibits FDA approved Fibroblasts Functional disorder Genetic Genotype Growth and Development function Hand Strength Health Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hematocrit procedure Heterozygote Home Homozygote Human Inbred Strains Mice Isomerase Knock-in Lead Lethal Genes Libraries Longevity Mediating Metabolic Diseases Missense Mutation Modeling Molecular Mus Muscle Weakness Mutation Names Neuropathogenesis Optics Paralysed Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Process Proteins Quality Control Quality of life Research Resources Rest Running Severities Symptoms Syndrome System Testing Time Triose-Phosphate Isomerase Ubiquitin Weight animal efficacy cohort dosage efficacy study efficacy testing experience fly human disease insertion/deletion mutation metabolic abnormality assessment metabolic phenotype mouse model multicatalytic endopeptidase complex muscle strength mutant neuromuscular novel therapeutics premature protein degradation protein function screening sex small molecule therapeutic development

项目摘要

Abstract/Project summary: TPI Df is a devastating untreatable childhood metabolic disease resulting in anemia, paralysis, irreversible brain damage and premature death. Numerous subtle amino acid substitutions in Triosephosphate Isomerase (TPI) are pathogenic and result in rapidly progressing multisystem disease. Importantly, pathogenic TPI Df mutations have been shown to result in protein that retains function but are unstable. Pathogenesis of numerous TPI DF mutations is known to result from increased turnover of the functioning protein by Protein Quality Control pathways (PQC). We have developed a human cellular TPI Df model of the “common” mutation and validated its use in optical screening. We are utilizing this model in an automated compound screening platform to identify first in class TPI Df small molecule therapies. To validate small molecule therapies there is a desperate need for a mammalian model of TPI Df. This proposed research will meet this need by using CRISPR to create a TPI Df model with the “common” mutation. A mouse model with construct validity for TPI Df that demonstrates analogous behavioral, physiological, and metabolic phenotypes is an important resource for the research community.

摘要/项目摘要： TPI Df 是一种毁灭性的、无法治愈的儿童代谢疾病，会导致贫血，瘫痪、不可逆转的脑损伤和过早死亡。磷酸丙糖异构酶 (TPI) 中的取代具有致病性，并会迅速导致重要的是，致病性 TPI Df 突变已被证实。结果显示，蛋白质保留了功能，但在许多发病机制中都不稳定。已知 TPI DF 突变是由于功能蛋白周转增加所致蛋白质质量控制途径 (PQC) 我们开发了人类细胞 TPI Df。 “常见”突变模型并验证了其在光学筛选中的用途。自动化化合物筛选平台中的该模型可识别一流的 TPI Df 迫切需要验证小分子疗法。这项拟议的研究将通过使用 TPI Df 的哺乳动物模型来满足这一需求。 CRISPR 创建具有“常见”突变的 TPI Df 模型具有“常见”突变的小鼠模型。构建 TPI Df 的有效性，证明类似的行为、生理和代谢表型是研究界的重要资源。