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：
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
项目类别：
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

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白细胞营养不良（ADLD）是一种致命的成人发作，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层lamin B1基因（LMNB1）的重复（ADLD-DUP），而小子集是由基因组引起的 LMNB1（ADLD-DEL）上游的删除。这两个突变都被认为会导致CNS LMNB1增加表达，是100％渗透剂，即所有患有突变的人都会发展出疾病。 lmnb1是a 核层的组成部分，在维持核结构，调节基因方面起着至关重要的作用表达和调节染色质定位。为什么增加了表达广泛的基因的表达由于LMNB1引起这种特定的脱髓鞘障碍是未知的。使用患者数据的组合，鼠和人类衍生的少突胶质细胞（OL）谱系细胞我们提出测试以下假设，即导致ADLD的层lamin B1的基因组重排会导致错误表达 lamin b1基因的我们将确定可能调节层蛋白的调节元素和机制 B1在体外和体内都使用新型小鼠模型表达。我们提出的实验将使我们能够全面地表征潜在的新型OL 可以为ADLD的组织类型特异性提供机械见解的调节元素和 OL功能和脱髓鞘疾病中的非编码调节元素。