Elucidating mechanisms involved in Lamin B1 mediated demyelination

阐明 Lamin B1 介导的脱髓鞘作用的机制

基本信息

批准号：
9077713
负责人：
Quasar S Padiath
金额：
$ 34.54万
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：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9077713
关键词：
Adult Affect Architecture Autonomic Dysfunction Binding Biology Brain CNS degeneration Cell Nucleus Cell physiology Cells Cessation of life Chromatin DNA Binding DNA Repair DNA biosynthesis Data Defect Demyelinating Diseases Demyelinations Disease Disease Progression Doxycycline Eukaryotic Cell Exhibits Fatty acid glycerol esters Gene Expression Gene Targeting Genes Genetic Transcription Histones Lamin B1 Lamins Lead Link Lipids Maps Mediating Multiple Sclerosis Mus Muscular Atrophy Myelin Nerve Neuraxis Nuclear Nuclear Inner Membrane Nuclear Lamina Nuclear Translocation Oligodendroglia Onset of illness Pathology Pathway interactions Phenotype Play Precipitation Process Proteins RNA Regulation Regulatory Pathway Role Signal Pathway Signal Transduction Spinal Cord Staging Symptoms Testing Therapeutic Trans-Activators Transcriptional Regulation Transgenic Mice Transgenic Organisms age related chromatin modification disease phenotype epigenetic regulation insight leukodystrophy lipid biosynthesis lipid metabolism motor disorder mouse model nervous system disorder next generation sequencing novel overexpression public health relevance research study spinal cord white matter transcription factor

项目摘要

DESCRIPTION (provided by applicant): Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. We have previously shown that ADLD is caused by duplications of the lamin b1 gene and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. We have recently demonstrated that transgenic (TG) mice with oligodendrocyte specific over-expression of lamin B1 exhibit severe vacuolar demyelination of the spinal cord that result in age dependent degenerative phenotypes reminiscent of ADLD. TG spinal cords showed dramatic reductions in the expression of multiple genes responsible for lipid synthesis, including the critical lipogenic transcription factors, SREBP1 and 2. This was accompanied by global increases in the repressive histone marks H3K9me3 and H3K27me3 in spinal cord oligodendrocytes. As myelin is made up of ~70% lipids, defects of lipid synthesis can result in severe demyelination. Consistent with our gene expression data, we observed a significant reduction of myelin enriched lipids that were specific to the spinal cord white matter. Our results identify lipid synthesis defects as a major component of the demyelination caused by lamin B1 over-expression and suggests a novel link between lamin B1 and lipid metabolism. While lipid dysregulation provides a cogent framework for explaining the demyelination observed in the transgenic mice, the mechanisms linking lamin B1 over-expression and lipid synthesis in oligodendrocytes are unknown and this proposal aims at identifying these pathways. We will test the hypothesis that lamin B1 modulates repressive histone marks to down regulate expression of specific target genes and examine whether lamin B1 over expression in oligodendrocytes results in the dysregulation of specific pathways that may impact oligodendrocyte function. We will also determine how modulating lamin B1 levels impacts the disease phenotype. The experiments that we have proposed will elucidate mechanisms linking lamin B1 over-expression, lipid dysregulation and the demyelination phenotype, results that will be critical in the identification of therapeutic pathways for ADLD. In addition, they will also provide insights into the basic biology of oligodendrocyte function that may help in understanding other common demyelinating diseases such as Multiple Sclerosis.

描述（由适用提供）：常染色体显性白细胞营养不良（ADLD）是一种致命的，进行性的成年疾病，其特征是自主和运动功能障碍，宽度CNS脱髓鞘。我们先前已经表明，ADLD是由层粘连蛋白B1基因的重复引起的，而层粘连蛋白B1的表达增加了疾病过程。在真核细胞中，层粘连蛋白B1是核薄片的主要构成，核层是与内部核膜相邻的纤维网状。核层保持核的结构完整性，并在必需的细胞过程中起作用，包括转录，DNA复制，DNA修复和表观遗传调节。我们最近证明，层状B1的少突胶质细胞特异性过表达的转基因（TG）小鼠表现出严重的脊髓真空脱髓鞘性，从而导致年龄依赖性的退化表型提醒ADLD。 TG脊髓显示了负责脂质合成的多个基因的表达急剧减少，包括关键的脂肪生成转录因子，SREBP1和2。这是通过反射性组蛋白标记H3K9ME3和H3K27ME3的全球增加来实现的。由于髓磷脂由约70％的脂质组成，因此脂质合成的缺陷会导致严重的脱髓鞘。与我们的基因表达数据一致，我们观察到特定于脊髓白质的髓磷脂富集的脂质的显着降低。我们的结果将脂质合成缺陷确定为由层粘连蛋白B1过表达引起的脱髓鞘的主要组成部分，并提出了层粘连蛋白B1与脂质代谢之间的新联系。虽然脂质失调为解释在转基因小鼠中观察到的脱髓鞘的框架提供了一个有说服力的框架，但在少突胶质细胞中连接层固定蛋白B1过表达和脂质合成的机制尚不清楚，并且该建议旨在识别这些途径。我们将检验以下假设：层lamin b1调节反射性组蛋白标记以降低调节特定靶基因的表达并检查lamin b1在少突胶质细胞中的表达上是否导致特定途径的失调，从而影响少突胶质细胞功能。我们还将确定调节层粘连蛋白B1水平如何影响疾病表型。我们提出的实验将阐明将层粘连蛋白B1过表达，脂质失调和脱髓鞘表型联系起来的机制，结果对于鉴定ADLD的治疗途径至关重要。此外，它们还将提供有关少突胶质功能的基本生物学的见解，这些生物可能有助于理解其他常见的脱髓脱叠疾病，例如多发性硬化症。