The role of lamins in transcription and redox homeostasis

描述（由申请人提供）：编码A型核纤层蛋白的人LMNA基因的突变引起称为核纤层蛋白病的广谱疾病。该建议集中于影响肌肉组织的层粘连蛋白病。核纤层蛋白是构成排列在核膜内侧的网络的细丝蛋白。我们发现突变核纤层蛋白导致核膜蛋白聚集在肌纤维的细胞质中。这在人类肌肉活检组织和来自我们的核纤层蛋白病果蝇模型的肌肉中都观察到。使用果蝇模型，我们发现参与细胞解毒的基因在疾病病理学早期阶段显著上调的基因中富集。此外，我们发现突变核纤层蛋白导致肌肉中的非典型代谢状态，称为“还原应力”。基于这些观察结果，我们假设核膜蛋白质的细胞质聚集引起抗氧化基因表达的诱导，从而改变肌肉的氧化还原状态，导致疾病病理。提出了两个具体目标来检验这一假设。具体目标1将确定核膜蛋白质的细胞质聚集在抗氧化基因表达的激活中的作用。这将通过调节蛋白质聚集体的代谢和测定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将确定还原应力在肌层蛋白病中的作用。这将通过调节肌纤维中的还原当量和测定肌肉表型的抑制来实现。总之，我们的研究结果将确定细胞质聚集和还原应力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剂。

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.