Novel epigenetic targets for silencing the Huntingtons disease mutation

沉默亨廷顿病突变的新表观遗传靶点

基本信息

批准号：
8960294
负责人：
Kyle Fink
金额：
$ 5.24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960294
关键词：
Alleles Basic Science Biological Assay Biological Models Boxing Brain California Cell Line Cell model Cells Chromosomal Stability Clinical Clinical Trials Collaborations DNA Restriction Enzymes DNA Sequence Discrimination Energy Transfer Environment Epigenetic Process Fellowship Fibroblasts Fluorescence Functional disorder Funding Future Gene Expression Gene Frequency Gene Mutation Gene Proteins Gene Targeting Gene-Modified Genes Genome Genotype Goals Hereditary Disease Human Human Cell Line Huntington Disease In Vitro Individual Knowledge Laboratories Length Libraries Life Location Measures Medical Mentors Methodology Minor Mission Mutation National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Nonhomologous DNA End Joining Pathway interactions Patients Persons Population Promoter Regions Proteins Reactive Oxygen Species Research Research Personnel Research Training Silene Single Nucleotide Polymorphism Site Supervision System Technology Testing Therapeutic Therapeutic Intervention Time Training Transcription Coactivator Transcription Repressor/Corepressor Translations Universities Work career development cost effective design gene therapy human Huntingtin protein in vitro Model knowledge base mitochondrial dysfunction multidisciplinary mutant nervous system disorder novel nuclease personalized medicine personalized therapeutic protein aggregation protein misfolding public health relevance repository therapy development vector

项目摘要

DESCRIPTION (provided by applicant): The proposed fellowship project will focus on optimizing an in vitro model system to test novel Huntington's disease (HD) therapeutics, creating a library of gene modification strategies aimed at silencing or correcting specifically th mutant gene in HD, and demonstrating robust and durable knockdown of HD-related cellular deficits using gene modification. The first of these three specific aims will be accomplished by validating a novel cellular model in which HD related dysfunction can be measured in a cost-effective, robust, and reproducible manner. This will be done by confirming mutant-allele-dependent deficits in fibroblast cultures isolated from HD patients. The second goal will be accomplished by first identifying specific target sites within the mutant allele for which gene modifying strategies can be developed. This will be done by identifying single nucleotide polymorphisms in the mutant allele that exist in greater than 40% of the Huntington's population and creating a library of transcription activator-like effectors (TALE) that can identify and silene or correct the mutant gene. By targeting single nucleotide polymorphisms that exist in the mutant allele, it will be possible in future studies to choose a patient-specific TALE from our library that will specifically suppress the mutant allele in that individual either independently o acting synergistically with a combination of TALEs suited for that persons genome. The results from this proposal will help further the knowledge of personalized treatment for patients suffering from HD and will help disseminate the function of the huntingtin gene in patient-specific human cell lines. A working library of TALE will be created that theoretically covers over 40% of the HD population and knowledge from this exploratory study can be applied to create personalized therapeutics for the vast majority of HD patients. This fellowship is in line with the mission of the National Institute of Neurological Disorders and Stroke as it will further the knowledge of the function of huntingtin gene, protein aggregation and misfolding, and the extent to which mitochondrial dysfunction occurs in a mutant allele- length dependent manner and the ability of these deficits to be corrected with gene modification. This fellowship will be conducted under the expert training of two senior principle investigators with extensive knowledge of genome targeting, gene therapy, and the development of therapeutic interventions for clinical trials. The work will be performed in collaboration between the two labs with direct supervision from the sponsor and co-sponsor. The fellowship will greatly enhance the knowledge base for personalized therapies, through careful examination of patient- specific gene modifiers for individuals suffering from genetic disorders.

描述（按应用程序提供）：拟议的奖学金项目将着重于优化一种体外模型系统，以测试新颖的亨廷顿sease（HD）疗法，创建一个旨在沉默或纠正规范规范特定特定的HD基因的基因修饰策略库通过新型模型验证HD相关的功能障碍，可以在具有成本效益的新型模型中验证HD相关的缺陷。通过首先识别特定靶标的HD患者，可以通过识别大于40％的亨廷顿tand的单个核苷酸多态性来开发基因修饰策略。（故事）靶向单个核苷酸多态性t在Tant Ellele中存在，在以后的研究中，可能会使我们的生长中的患者特定的皮革Tare take tate tate the Lirary的患者特异性的皮革，该皮革将在该独立的OCTINS Synergistrys中与Tales的组合组合在该独立的OCTING中。适合该人的基因组。该探险家的HD人口中有40％的人口和知识，以创建人类NT。国家神经系统疾病和中风研究所的使命是它的含量和错误折叠的作用，以及mitchondrial功能障碍以突变等位基因长度长度的持久方式以及这些S纠正基因修饰的能力的程度。该奖学金将被归咎于在两名高级原则研究者的专家培训下，对基因组靶向的知识以及Apeutic 2赞助者的发展将大大提高个性化疗法的基础，您会仔细检查患者特异性基因或患有遗传疾病的个体。