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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

基本信息

批准号：
10829590
负责人：
Quasar S Padiath
金额：
$ 4.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10829590
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

项目摘要

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.

抽象的常染色体显性脑白质营养不良 (ADLD) 是一种致命的、成人发病的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引起的涉及核纤层蛋白 B1 基因 (LMNB1) 的重复 (ADLD-dup)，而一小部分是由基因组引起的 LMNB1 上游缺失 (ADLD-del)。这两种突变都被认为会导致中枢神经系统 LMNB1 增加表达并且是 100% 渗透性，即所有具有突变的个体都会罹患疾病。 LMNB1 是核纤层的组成部分，在维持核结构、调节基因方面发挥着关键作用表达和调节染色质定位。为什么广泛表达的基因的表达增加由于 LMNB1 导致这种特定的脱髓鞘疾病尚不清楚。我们结合患者数据、小鼠和人源性少突胶质细胞 (OL) 谱系细胞提出建议检验涉及 Lamin B1 的基因组重排导致 ADLD 导致错误表达的假设核纤层蛋白 B1 基因。我们将确定可能调控核纤层蛋白的调控元件和机制使用新型小鼠模型在体外和体内表达 B1。我们提出的实验将使我们能够全面表征潜在的新型 OL 调节元件，可以为 ADLD 的组织类型特异性和作用提供机制见解 OL 功能和脱髓鞘疾病中的非编码调控元件。