The role of nuclear envelope protein NET39 in skeletal muscle function and diseases

项目摘要/摘要 核膜蛋白是维持核结构、基因表达和染色质所必需的 组织。核膜蛋白和核层蛋白的突变会导致许多人类疾病， 其中许多涉及骨骼肌缺陷，如Emery-Dreifuss肌营养不良症(EDMD)。虽然 导致这些疾病的基因突变是已知的，其分子机制 核包膜中的微扰导致疾病仍然没有被很好地理解。此外，目前还不清楚为什么 普遍表达的核膜蛋白的突变会导致组织特异性的发病机制，例如 横纹肌特有的缺陷。我们的实验室最近发现核膜跨膜蛋白39 (NET39)是核膜结构和功能的肌肉特异性调节因子。NET39在 EDMD患者肌肉活检和Net39基因缺失导致小鼠核膜畸形，先天性 肌病和青少年致命性。在核膜内，NET39与核膜的几个组成部分相互作用 核膜，如LEMD2。我们对NET39的研究为解开长期存在的 为什么横纹肌在核膜相关疾病中受到特殊影响的谜题。我们假设 NET39在EDMD的发病机制中发挥着骨骼肌特异性的关键作用。这个项目的总体目标是 是为了确定NET39的功能及其与其他核膜蛋白在调控核中的相互作用 探讨包膜完整性和基因表达在骨骼肌内稳与疾病中的作用 NET39在EDMD和其他椎板病中的表达。最终，我们希望利用这些见解来开发新的 EDMD及相关椎板病的治疗策略。

Project Summary/Abstract Nuclear envelope proteins are essential for maintaining nuclear architecture, gene expression and chromatin organization. Mutations in nuclear envelope proteins and nuclear lamins cause numerous human diseases, many of which involve in skeletal muscle defects such as Emery-Dreifuss muscular dystrophy (EDMD). Although the genetic mutations responsible for these diseases are known, the molecular mechanisms whereby perturbations in the nuclear envelope cause disease are still not well understood. Moreover, it is still unclear why mutations in ubiquitously expressed nuclear envelope proteins lead to tissue-specific pathogenesis such as striated muscle-specific defects. Our lab recently showed that the nuclear envelope transmembrane protein 39 (NET39) is a muscle-specific regulator of nuclear envelope structure and function. NET39 is downregulated in EDMD patient muscle biopsies, and deletion of Net39 in mice caused nuclear envelope deformations, congenital myopathy and juvenile lethality. Within the nuclear envelope, NET39 interacts with several components of the nuclear envelope such as LEMD2. Our studies of NET39 provide an entry point to unravel the long-standing puzzle of why striated muscle is specifically affected in nuclear envelope related diseases. We hypothesize that NET39 plays a pivotal skeletal muscle-specific role in the pathogenesis of EDMD. The overall goals of this project are to define the functions of NET39 and its interactions with other nuclear envelope proteins in regulating nuclear envelope integrity and gene expression during skeletal muscle homeostasis and disease, and to explore the role of NET39 in EDMD and other laminopathies. Ultimately, we hope to use these insights to develop new therapeutic strategies for EDMD and related laminopathies.