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Investigating the role of NMD in Nonsense Mutation Biology and Therapeutic Strategies

研究 NMD 在无义突变生物学和治疗策略中的作用

基本信息

批准号：
10708825
负责人：
Margaret Michicich
金额：
$ 4.77万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708825
关键词：
Alleles Animal Model Animals Bioinformatics Biological Assay Biological Models Biology Caffeine Cell physiology Cells Clinical Research Clinical Trials Communication Research Congenic Mice Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Disease Drug Combinations Duchenne muscular dystrophy Embryo Failure Forskolin Future Genes Genetic Diseases Genotype Heterogeneity Heterozygote Human Human Genetics In Vitro Inbred CFTR Mice Intestines Location Low Prevalence Measures Modeling Mus Mutation Nonsense Codon Nonsense Mutation Nonsense-Mediated Decay Organoids Pathway interactions Patients Pharmaceutical Preparations Phenotype Predisposition Process Proteins Resistance Role Science Severities Severity of illness Small Intestines Swelling Techniques Terminator Codon Testing Therapeutic Tissues Toxic effect Training Transcript Translating Translational Research Translations Treatment Efficacy Work amlexanox antibiotic G 418 beta Thalassemia burden of illness career cell type cystic fibrosis mouse cystic fibrosis patients drug testing efficacy testing human tissue improved in vitro Model in vivo in vivo Model in vivo evaluation inhibitor mouse model mutation correction novel pharmacologic pre-clinical precision medicine premature prevent protein folding protein function resistance mutation restoration treatment response

项目摘要

There is a great need for treatments for diseases caused by nonsense mutations. In the context of Cystic Fibrosis (CF), caused by mutations in the CFTR gene, patients with two nonsense alleles lack CFTR-specific treatments. CF provides a useful context in which to study nonsense mutation biology as CF is a well characterized genetic disease, has numerous model systems, and has dozens of nonsense mutations within CFTR. Nonsense-mediated decay (NMD) is the cellular process that degrades transcripts containing premature termination codons caused by nonsense mutations. NMD acts as a treatment barrier in nonsense mutation conditions by preventing protein from being translated as few nonsense transcripts remain in the cell. NMD, however, does not affect all nonsense transcripts equally. NMD efficiency has been suggested to vary by tissue, cell type, and even by patient. Furthermore, nonsense mutations in specific locations within the transcript escape NMD. This proposal aims to study the heterogeneity of NMD in CF nonsense mutations and the pharmacological correction of CF nonsense mutations. Novel mouse models containing CF nonsense mutations predicted to escape NMD will be developed. Using these NMD resistant models, NMD efficiency will be measured and compared to existing CF models containing NMD susceptible nonsense mutations. Using existing and new CF nonsense mouse models, pharmacological correction of nonsense mutations will be studied. NMD inhibitors will be investigated, as well as readthrough agents (capable of triggering the readthrough of premature stop codons), and CFTR modulators (which promote CFTR protein folding and function) will be tested independently and in combination in mouse and human intestinal organoids and ultimately in vivo in nonsense mutation mouse models. The best pharmacological combination may differ for each genotype or by NMD phenotype. Studying the role of NMD in CF heterogeneity and CF nonsense mutation correction may elucidate better therapeutic strategies and provide evidence for pursuing a precision medicine approach in CF. The training plan outlined in this proposal will strongly support a successful transition to a career in translational research for the trainee. The training plan includes activities relating to science communication, clinical and translational research, preclinical in vivo animal techniques, and bioinformatics.

对无义突变引起的疾病的治疗有很大的需求。在囊肿的背景下