The role of lamins in transcription and redox homeostasis

描述(由申请人提供)：编码A型椎板的人类LMNA基因突变会引起一系列称为椎板病的疾病。这项建议侧重于肌肉组织受到影响的椎板病变。层粘连蛋白是组成排列在核膜内侧的网络的细丝蛋白。我们发现，突变的板层导致核膜蛋白聚集在肌肉纤维的细胞质中。这在人类肌肉活检组织和我们的果蝇椎板病模型的肌肉中都观察到了。利用果蝇模型，我们发现参与细胞解毒的基因在疾病病理的早期阶段显著上调的基因中丰富。此外，我们还发现突变的Lamins会在肌肉中引起一种非典型的代谢状态，称为“还原应激”。基于这些观察，我们假设核膜蛋白的细胞质聚集导致抗氧化基因表达的诱导，从而改变肌肉的氧化还原状态，促进疾病病理。为了检验这一假说，本文提出了两个具体目标。特异目的1将确定核膜蛋白胞质聚集在激活抗氧化基因表达中的作用。这将通过调节蛋白质聚集体的新陈代谢，分析抗氧化基因表达的变化和肌肉表型的抑制来实现。具体目标2将确定减少应力在肌肉椎板病中的作用。这将通过调节肌肉纤维中的还原当量和分析肌肉表型的抑制来实现。综上所述，我们的发现将确定细胞质聚集体和减少应激在肌肉疾病病理中的作用。此外，我们将确定抑制肌肉表型的化合物作为潜在的治疗药物。

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.