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.

项目概要自从我们在 2011 年发现重复相关的非 ATG (RAN) RAN 翻译以来，我们和其他人已经表明 RAN 蛋白在九种不同的扩张障碍中积累。蛋白质，可以从有义和反义扩展转录物中表达，在疾病相关人体组织中积累，包括脊髓小脑共济失调 8 型 (SCA8) 我们现在有证据表明多聚丝氨酸和多聚亮氨酸 RAN 蛋白。聚集在一组脊髓小脑共济失调（SCA1、2、3、6 和 7）中，其中 CAG·CTG 扩展突变位于聚谷氨酰胺开放阅读框中。此外，我们还有。开发了 AAV 和小分子方法来抑制 RAN 翻译，我们将使用这些方法。工具和遗传学方法来检验我们的中心假设，即 RAN 蛋白病理学是编码多聚谷氨酰胺的 CAG·CTG 扩张障碍和抑制 PKR 通路将降低 RAN 蛋白水平并减轻疾病。我们将通过三个具体目标来解决我们的中心假设 (1) 检验以下假设： RAN 蛋白导致多聚谷氨酰胺编码引起的脊髓小脑共济失调 (SCA) CAG·CTG重复扩增突变(2)检验SCA和HD RAN的假设。蛋白质是有毒的，PKR 抑制会降低 RAN 蛋白质水平并改善细胞 HD 和 SCA3 iPSC 衍生细胞中的表型 (3)：检验 RAN 蛋白的假设利用遗传因素对小鼠中的 HD 和 SCA3 表型做出贡献，与 PolyGln 效应无关综合起来，这些具体目标将决定。 RAN 蛋白对 HD、SCA3 和 CAG·CTG 重复扩增障碍的贡献将 PKR 抑制描述为这一大类疾病的潜在治疗方法毁灭性的重复扩张疾病。