Delineating the functional impact of recurrent repeat expansions in ALS using integrative multiomic analysis

使用综合多组学分析描述 ALS 中反复重复扩增的功能影响

• 批准号: 10776994
• 负责人: Gamze Gursoy
• 金额: $ 32.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10776994
• 关键词: 3-Dimensional; ALS patients; Accounting; Address; Affect; Amyotrophic Lateral Sclerosis; Area; Autopsy; Base Pairing; Base Sequence; Brain; C9ORF72; Cells; Cessation of life; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA Repeat Expansion; DNA Sequence; Data; Data Set; Deglutition; Diagnosis; Disease; Disease Progression; Expanded DNA Repeat; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Variation; Genome; Genotype-Tissue Expression Project; Individual; Introns; Joints; Life Expectancy; Link; Malignant Neoplasms; Molecular; Motor Neurons; Movement; Multiomic Data; Muscle; Muscle Cells; Muscle Weakness; Mutation; Neurodegenerative Disorders; Neurons; Pathogenesis; Population; Prognosis; Quantitative Trait Loci; RNA; Recurrence; Regulation; Regulator Genes; Regulatory Element; Research; Respiratory Failure; Scientist; Single Nucleotide Polymorphism; Spinal Cord; Surveys; Testing; Time; Tissue-Specific Gene Expression; Tissues; Untranslated RNA; Validation; Work; autism spectrum disorder; brain tissue; cohort; computerized tools; data integration; effective therapy; genome sequencing; genome-wide; genomic data; improved; mouse model; multiple omics; new therapeutic target; novel; protein aggregation; single nucleus RNA-sequencing; targeted treatment; tool; whole genome

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects nerve cells in the brain and spinal cord, resulting in muscle weakness, difficulty speaking and swallowing, and eventually, respiratory failure. There is no known cure and the average life expectancy of an ALS patient is 3-5 years from the time of diagnosis. Therefore, it is important to identify the genetic alterations that are involved in the molecular pathogenesis of ALS in order to develop targets for therapeutics. Genome-wide occurrence of DNA repeat expansions has been identified as a common genetic cause or marker of several neurodegenerative diseases, including ALS. Here we propose to survey the whole genome sequencing data from a population of ALS patients and healthy individuals for recurrent repeat expansions, correlate these findings with gene expressions, and finally study mechanisms of regulation of identified genes by integration of gene expression, chromatin accessibility, and 3D genome organization data. We hypothesize that many of the overlooked repeat expansions are located in the non-coding regions of the genome and are involved in regulation of genes that might contribute to the death of motor neurons. To this end, we will first identify the recurrent repeat expansions that act as tissue- specific expression quantitative trait loci using GTEx data. We will then integrate multi-omics data from ALS patients with 3D genome data from the 4DN project to identify gene regulatory circuitry. We envision that the proposed work will allow scientists to generate experimentally testable hypotheses by creating a link between non-coding repeat expansions and genes in a tissue-specific manner and help identify new therapeutic targets.

项目摘要 肌萎缩性侧性硬化症（ALS）是一种进行性神经退行性疾病，影响神经细胞 大脑和脊髓，导致肌肉无力，说话和吞咽困难，最终 呼吸衰竭。没有已知的治愈方法，ALS患者的平均预期寿命比 诊断时间。因此，重要的是要识别分子涉及的遗传改变 ALS的发病机理，以开发治疗靶标。 DNA重复的全基因组发生 扩张已被确定为几种神经退行性疾病的常见遗传原因或标志物， 包括ALS。在这里，我们建议调查来自ALS患者人群的整个基因组测序数据 和健康的个体，以反复重复扩张，将这些发现与基因表达相关联，以及 最后，通过整合基因表达，染色质的整合鉴定基因调节的调节机制 可访问性和3D基因组组织数据。我们假设许多被忽略的重复扩展 位于基因组的非编码区域，参与可能有助于贡献的基因的调节 运动神经元死亡。为此，我们将首先确定充当组织的反复重复扩张 使用GTEX数据的特定表达定量性状基因座。然后，我们将整合来自ALS的多摩斯数据 来自4DN项目的3D基因组数据的患者鉴定基因调节回路。我们设想 拟议的工作将使科学家通过在 以组织特异性的方式进行非编码重复扩张和基因，并有助于识别新的治疗靶标。