The role of lamins in transcription and redox homeostasis

核纤层蛋白在转录和氧化还原稳态中的作用

基本信息

批准号：
8691734
负责人：
Lori L Wallrath
金额：
$ 19.25万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8691734
关键词：
Accounting Adipose tissue Affect Antioxidants Basic Science Binding Binding Sites Biological Assay Biopsy Cardiomyopathies Cell Nucleus Cells Collection Cytoplasm Cytoplasmic Protein Dilated Cardiomyopathy Disease Drosophila genus Drug Metabolic Detoxication Filament Finding by Cause Gene Expression Genes Genetic Genetic Transcription Glutathione Glutathione Disulfide Glycine decarboxylase Homeostasis Human Intermediate Filaments Lamin Type A Lamins Learning Link Metabolic Metabolism Modeling Muscle Muscle Fibers Muscular Dystrophies Mutation Myopathy Nuclear Envelope Oxidation-Reduction Oxidative Stress Pathology Patients Phenotype Protein Binding Proteins Research Role Scientist Side Staging Stress Testing Therapeutic Tissues base disease-causing mutation env Gene Products gene discovery insight mutant novel protein aggregate protein aggregation public health relevance research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mutations in the human LMNA gene encoding A-type lamins give rise to a broad spectrum of diseases termed laminopathies. This proposal focuses on laminopathies in which muscle tissue is affected. Lamins are filament proteins that make up a network that line the inner side of the nuclear envelope. We discovered that mutant lamins cause aggregates of nuclear envelope proteins to accumulate in the cytoplasm of muscle fibers. This was observed in both human muscle biopsy tissues and muscle from our Drosophila model of laminopathies. Using the Drosophila model, we discovered that genes involved in cellular detoxification are enriched among those dramatically up-regulated in early stages of disease pathology. In addition, we discovered that mutant lamins cause an atypical metabolic state in muscle termed 'reductive stress'. Based on these observations, we hypothesize that cytoplasmic aggregation of nuclear envelope proteins cause the induction of anti-oxidant gene expression that alters the redox status of muscle, contributing to disease pathology. Two specific aims are proposed to test this hypothesis. Specific Aim 1 will determine the role of cytoplasmic aggregation of nuclear envelope proteins in the activation of anti-oxidant gene expression. This will be accomplished by regulating the metabolism of protein aggregates and assaying for changes in anti-oxidant gene expression and suppression of muscle phenotypes. Specific Aim 2 will determine the role of reductive stress in muscle laminopathies. This will be accomplished by modulating the reducing equivalents in muscle fibers and assaying for suppression of muscle phenotypes. Taken together, our findings will determine the role of cytoplasmic aggregates and reductive stress in muscle disease pathology. In addition, we will identify compounds that suppress the muscle phenotypes as potential therapeutics.

描述（由申请人提供）：编码A型层粘连蛋白的人LMNA基因中的突变会引起广泛的称为椎板病的疾病。该提议的重点是肌肉组织受到影响的椎板病。 lamins是构成核包膜内侧网络的细丝蛋白。我们发现突变层层粘蛋白会导致核包膜蛋白聚集在肌肉纤维的细胞质中。这在我们的果蝇模型的椎体病模型中观察到了这一点。使用果蝇模型，我们发现参与细胞排毒的基因在疾病病理的早期阶段大大上调的基因富集。此外，我们发现突变层层板在称为“还原应力”的肌肉中引起非典型代谢状态。基于这些观察结果，我们假设核包膜蛋白的细胞质聚集导致诱导抗氧化基因表达，从而改变了肌肉的氧化还原状态，从而导致疾病病理。提出了两个具体目标来检验这一假设。具体的目标1将确定核包膜蛋白的细胞质聚集在抗氧化基因表达激活中的作用。这将通过调节蛋白质聚集体的代谢以及抗氧化基因表达的变化和抑制肌肉表型的变化来实现。具体的目标2将确定还原应力在肌肉层流中的作用。这将通过调节肌肉纤维中的减少等效物和抑制肌肉表型的测定来实现。综上所述，我们的发现将确定细胞质骨料的作用和还原应激在肌肉疾病病理学中的作用。此外，我们将确定抑制肌肉表型的化合物作为潜在的治疗剂。