Comparison of HD and HDL2 mouse models to reveal common mechanisms of pathogenesis

HD 和 HDL2 小鼠模型的比较揭示共同的发病机制

基本信息

批准号：
10347570
负责人：
RUSSELL L MARGOLIS
金额：
$ 45.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-09-15 至 2024-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347570
关键词：
Adult Age-Months Alleles Antibodies Appearance Autopsy Bacterial Artificial Chromosomes Behavior Biological Assay Brain Brain region Brain-Derived Neurotrophic Factor CRISPR/Cas technology Cell model Cessation of life Chromosomes Clinical Clinical Trials Cognition Disorders Corpus striatum structure Deposition Development Disease Emotional disorder Exons Funding Gene Expression Profile Genes Goals Heterozygote Human Huntington Disease Immune Inherited Knock-in Knock-in Mouse Lead Length Measures Mitochondria Modeling Molecular Motor Movement Disorders Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Protein Open Reading Frames Pathogenesis Pathogenicity Pathway interactions Patients Peptides Phenotype Process Proteomics RNA Research Design Role Stains Synapses Testing Therapeutic Intervention Time Tissues Toxic effect Transcript Transgenic Organisms Triplet Multiple Birth Validation Withdrawal brain cell design experimental study falls gene function genetic testing induced pluripotent stem cell junctophilin loss of function motor behavior motor disorder mouse model neuroimaging neuropathology neurotoxicity new therapeutic target polyglutamine preclinical development protein aggregation therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary HD is an autosomal dominant neurodegenerative disease, characterized by movement, cognitive and emotional disorders, with relentless progression to death. There is currently no disease-modifying treatment for HD. Though clinical suppression strategies are in clinical trials or preclinical development, the efficacy and tolerability of these treatments remains unknown, hence there is great need to search, in parallel, for other therapeutic targets. To facilitate prioritizing HD pathways for therapeutic interventions, we have launched an effort to compare HD with Huntington’s disease-like 2 (HDL2). HDL2, discovered and genetically defined by our group, is an adult onset autosomal dominant neurodegenerative disorder that is clinically, genetically, and neuropathologically remarkably similar to HD. Experts cannot distinguish between the two disorders without genetic testing. Both disorders are caused by a repeat expansion mutation; the mutation in HDL2 is caused by a CTG/CAG expansion on chromosome 16q24 in the gene junctophilin-3. Like HD, expanded tracks of polyglutamine probably are the key factor in HDL2 pathogenesis. However, also like HD, RNA transcripts containing the expanded repeat and a loss-of- function the gene in which the repeat is found likely also contribute to pathogenesis. We hypothesize that HD and HDL2 share pathogenic pathways, and that detecting these pathways will lead to further understanding of both disorders and the development of new therapeutic targets. As part of our efforts to test this hypothesis, we propose to use CRISPR/Cas9 and ssDNA donors to generate an HDL2 knock-in (KI) mouse model with either 14 (normal) or ~100 triplets (mutation). We will compare these new mouse lines with the similar KI HD lines Hdh10/+ and HDh111/+. In Aim 1, we will test the hypothesis that the HDL2 and HD expansion mutations results in a similar phenotype by comparing the behavior and neuropathology of HDL2 and HD KI lines. In Aim 2, we will test the hypothesis that similar molecular mechanisms are associated with HD and HDL2 pathogenesis by using RNAseq to compare the pattern of gene expression in the HDL2 and HD model mice. If successful, this project will provide the basis for detailed studies designed to find new therapeutic targets for both HD and HDL2.

项目概要 HD 是一种常染色体显性神经退行性疾病，以运动为特征，情绪障碍，不断进展至死亡目前尚无缓解疾病的方法。尽管 HD 的临床抑制策略尚处于临床试验或临床前开发阶段，但这些治疗方法的功效和耐受性仍然未知，因此非常需要寻找与其他治疗目标平行，为了促进治疗干预的优先顺序，我们发起了一项研究，将 HD 与发现的亨廷顿病样 2 (HDL2) 进行比较。我们的团队从遗传学上定义，是一种成人发病的常染色体显性神经退行性疾病在临床、遗传和神经病理学上与 HD 相似，专家无法区分。两种疾病之间的差异无需进行基因检测，这两种疾病都是由重复扩张引起的。 HDL2 突变是由基因 16q24 上的 CTG/CAG 扩增引起的与 HD 一样，聚谷氨酰胺的扩展轨道可能是 HDL2 的关键因素。然而，也像 HD 一样，RNA 转录物含有扩展的重复序列和丢失的- 发现重复的基因的功能也可能有助于发病机制。我们认为 HD 和 HDL2 具有共同的致病途径，并且检测这些途径将有助于进一步了解这两种疾病并开发新的治疗靶点。为了检验这一假设，我们建议使用 CRISPR/Cas9 和 ssDNA 供体来生成 HDL2 敲入 (KI) 小鼠模型具有 14 个（正常）或约 100 个三联体（突变）我们将比较这些模型。具有相似 KI HD 品系 Hdh10/+ 和 HDh111/+ 的新小鼠品系在目标 1 中，我们将检验假设。通过比较行为和 HDL2 和 HD 扩展突变会导致相似的表型 HDL2 和 HD KI 系的神经病理学在目标 2 中，我们将检验类似分子的假设。通过使用 RNAseq 比较 HD 和 HDL2 发病机制的模式如果成功，该项目将为HDL2和HD模型小鼠中的基因表达提供基础。旨在寻找 HD 和 HDL2 新治疗靶点的详细研究。