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Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

RAN 蛋白对 HD、SCA3 和其他 CAG.CTG 扩展疾病的贡献

基本信息

批准号：
10450786
负责人：
Monica Banez-Coronel
金额：
$ 61.09万
依托单位：
UNIVERSITY OF FLORIDA
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：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450786
关键词：
3&apos Untranslated Regions Address Affect Antibodies Ataxia Autopsy Bacterial Artificial Chromosomes Behavioral Brain C-terminal C9ORF72 CAG repeat CRISPR/Cas technology Categories Cells Collection Cultured Cells Development Disease Disease Progression FDA approved Functional disorder Genetic Human Huntington Disease Individual Introns Knock-in Mouse LY6E gene Length MJD1 protein Metformin Molecular Mus Mutation Neurologic Neurons Open Reading Frames Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Protein Biosynthesis Proteins RNA Reading Frames Severity of illness Site Spinocerebellar Ataxias Testing Therapeutic Time Tissues Toxic effect Transcript Transgenic Organisms Translations design experimental study frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic approach human disease human tissue improved in vivo induced pluripotent stem cell inhibitor insight new therapeutic target novel novel strategies novel therapeutic intervention polyglutamine protein kinase R small molecule tool transcriptomics

项目摘要

Project Summary Since we discovered repeat associated non-ATG (RAN) RAN translation in 2011, we and others have shown that RAN proteins accumulate in nine different expansion disorders. These proteins, which can be expressed from both sense and antisense expansion transcripts, accumulate in disease-relevant human tissues including spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD). We now have evidence that polySer and polyLeu RAN proteins accumulate in a group of spinocebellar ataxias (SCA1, 2, 3, 6 and 7) in which the CAG·CTG expansion mutations are located in polyGln open reading frames. Additionally, we have developed AAV and small molecule approaches to inhibit RAN translation. We will use these tools and genetic approaches to test our central hypotheses that RAN protein pathology is a common feature shared across polyglutamine encoding CAG·CTG expansion disorders and that inhibiting the PKR pathway will reduce RAN protein levels and mitigate disease. We will address our central hypothesis in three specific aims (1) To test the hypothesis that RAN proteins contribute to spinocerebellar ataxias (SCAs) caused by polyglutamine encoding CAG·CTG repeat expansion mutations. (2) To test the hypothesis that SCA and HD RAN proteins are toxic and PKR inhibition will decrease RAN protein levels and improve cellular phenotypes in HD and SCA3 iPSC derived cells (3) : To test the hypothesis that RAN proteins contribute to HD and SCA3 phenotypes in mice independent of polyGln effects using genetic and pharmacological approaches. Taken together these specific aims will determine the contribution of RAN proteins to HD,SCA3 and CAG·CTG repeat expansion disorders and characterize PKR inhibition as a potential therapeutic approach for this large class of devastating repeat expansion diseases.

项目总结