项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

MILLER, DANIEL L

项目受资助机构

UNIVERSITY OF FLORIDA

立项年度

2020

立项时间

未公开

项目编号

5R37NS040389-17

研究期限

未知 / 未知

项目级别

国家级

受资助金额

670405.00美元

学科

ALS; Acquired Cognitive Impairment; Alzheimer's Disease Related Dementias (ADRD); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Biotechnology; Brain Disorders; Dementia; Frontotemporal Dementia (FTD); Genetics; Neurodegenerative; Neurosciences; Rare Diseases;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

RANUM, LAURA P.W

参与机构

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

项目标书摘要：? DESCRIPTION (provided by applicant): Research on spinocerebellar ataxia type 8 (SCA8) supported by this application has led to two discoveries that fundamentally change our understanding of how a broad category of microsatellite expansion mutations are expressed. First, we demonstrated that the SCA8 CTG?CAG expansion is bidirectionally transcribed1. This was the first demonstration that a single expansion mutation could lead to the expression and accumulation of toxic CUG and CAG expansion RNAs and a CAG-encoded polyGln expansion protein1. Second, we discovered that the canonical rules of translation do not apply for CTG?CAG repeats and that CAG and CUG expansion transcripts can express homopolymeric expansion proteins in all three frames without an AUG start codon2. We showed this repeat associated non-ATG (RAN) translation is hairpin-dependent, occurs without frameshifting or RNA editing and is observed in cell culture and SCA8 patient tissues2. RAN translation also occurs in myotonic dystrophy type 1 (DM1)2, C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD9)3-5, and fragile X tremor ataxia syndrome (FXTAS)6. The discoveries of bidirectional transcription and RAN translation change our understanding of how genes are expressed and highlight the need for therapies that target both sense and antisense transcripts as well as RAN proteins. Our central hypothesis is that both RNA and RAN gain of function (GOF) contribute to SCA8 and can be mitigated by therapies based on MBNL1 overexpression or RNA knockdown. Our specific aims will test the following hypotheses: 1) RNA gain of function and RAN translation contribute to SCA8; 2) RAN translation can be modulated by MBNL proteins and stress pathways; 3) antisense oligo (ASO) knockdown of ATXN8 and ATXN8OS will block RNA and RAN effects and reverse disease in an SCA8 mouse model.