Elucidating Regulatory Mechanisms of Lamin B1 Expression in Autosomal Dominant Leukodystrophy

阐明常染色体显性脑白质营养不良中核纤层蛋白 B1 表达的调节机制

• 批准号: 10582856
• 负责人: Quasar S Padiath
• 金额: $ 40.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582856
• 关键词: Ablation; Adult; Age; Architecture; Astrocytes; Automobile Driving; Autopsy; Behavioral; Binding; Binding Sites; Bioinformatics; Biological Models; Biology; Brain; Brain region; CCCTC-binding factor; CRISPR/Cas technology; Cell Line; Cell Lineage; Cell model; Cells; Cessation of life; Chromatin; Complex; DNA Sequence Rearrangement; Data; Demyelinating Diseases; Demyelinations; Disease; Disease Pathway; Elderly; Elements; Epigenetic Process; Family; Fibroblasts; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Genomic Segment; Genomics; Human; In Vitro; Individual; LMNB1 gene; Lamin B1; Late-Onset Disorder; Location; Maps; Mediating; Molecular; Mus; Muscular Atrophy; Mutation; Myelin; Nerve; Neurons; Nuclear; Nuclear Lamina; Nucleic Acid Regulatory Sequences; Oligodendroglia; Pathway interactions; Patients; Phenotype; Play; Polycomb; Positioning Attribute; Proteins; Regulation; Regulatory Element; Role; Specificity; Testing; Tissues; Transcriptional Silencer Elements; Untranslated RNA; autosome; brain tissue; cell type; disease phenotype; experimental study; genomic locus; in vivo; insight; leukodystrophy; member; motor disorder; mouse model; nervous system disorder; novel; oligodendrocyte lineage; overexpression; prevent; recruit; segregation; transcription factor; transcriptomics; white matter

Abstract Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult onset, progressive neurological disease that is characterized by widespread CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications (ADLD-dup) involving the lamin B1 gene (LMNB1) while a small subset is caused by genomic deletions upstream of LMNB1 (ADLD-del). Both these mutations are thought to cause increased CNS LMNB1 expression and are a 100% penetrant i.e., all individuals with the mutation develop the disease. LMNB1 is a component of the nuclear lamina and plays a critical role in maintaining nuclear architecture, regulating gene expression and modulating chromatin positioning. Why increased expression of a widely-expressed gene such as LMNB1 causes such a specific demyelination disorder is unknown. Using a combination of patient data, murine and human derived oligodendrocyte (OL) lineage cells we propose to test the hypothesis that genomic rearrangements involving Lamin B1 that cause ADLD result in mis-expression of the lamin B1 gene. We will identify regulatory elements and mechanisms that can potentially regulate Lamin B1 expression both in vitro and in vivo using a novel mouse model. The experiments we have proposed will allow us to comprehensively characterize a potentially novel OL regulatory element that can provide mechanistic insights into the tissue type specificity of ADLD and the role of non-coding regulatory elements in OL function and demyelinating diseases.

摘要 常染色体显性脑白质营养不良（ADLD）是一种致命的，成人发病，进行性神经系统疾病， 以广泛的中枢神经系统脱髓鞘为特征。大多数ADLD病例是由串联基因组 复制（ADLD-dup）涉及核纤层蛋白B1基因（LMNB 1），而一小部分是由基因组 LMNB 1上游缺失（ADLD-del）。这两种突变都被认为会导致CNS LMNB 1增加 表达并且是100%渗透剂即，所有携带突变基因的个体都会患病LMNB 1是一个 它是核纤层的组成部分，在维持核结构、调节基因表达、 表达和调节染色质定位。为什么一个广泛表达的基因的表达增加， 因为LMNB 1引起这种特定的脱髓鞘疾病是未知的。 使用患者数据的组合，鼠和人来源的少突胶质细胞（OL）谱系细胞，我们提出 为了检验涉及导致ADLD的核纤层蛋白B1的基因组重排导致错误表达的假设， 核纤层蛋白B1基因我们将确定可能调节核纤层蛋白的调节元件和机制， 使用新型小鼠模型进行体外和体内B1表达。 我们提出的实验将使我们能够全面表征一种潜在的新型OL 调节元件，可以提供对ADLD的组织类型特异性的机制见解， OL功能和脱髓鞘疾病中的非编码调节元件。