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

核膜蛋白NET39在骨骼肌功能和疾病中的作用

基本信息

批准号：
10581457
负责人：
Ning Liu
金额：
$ 46.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581457
关键词：
Adolescent Adult Affect Architecture Biopsy Cell Cycle Progression Cell Nucleus Chromatin Cytoplasm DNA Damage DNA Sequence Alteration DNA biosynthesis Defect Development Disease Emery-Dreifuss Muscular Dystrophy Foundations Gene Delivery Gene Expression Gene Transfer Techniques Genome Goals Homeostasis Integral Membrane Protein Lead Limb-Girdle Muscular Dystrophies Lipid Bilayers Maintenance Mediating Membrane Proteins Molecular Mus Muscle Muscle function Muscular Dystrophies Mutation Myopathy Nuclear Nuclear Envelope Nuclear Lamin Nuclear Protein Nuclear Proteins Nuclear Structure Nucleoplasm Pathogenesis Pathology Patients Play Progeria Proteins Role Skeletal Muscle Striated Muscles Structure Supportive care Syndrome Tissues Work congenital myopathy env Gene Products human disease insight mouse model myocyte-specific enhancer-binding-factor 2C novel therapeutic intervention novel therapeutics overexpression segregation single nucleus RNA-sequencing transcription factor

项目摘要

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.

项目概要/摘要核膜蛋白对于维持核结构、基因表达和染色质至关重要组织。核膜蛋白和核纤层蛋白的突变导致多种人类疾病，其中许多与骨骼肌缺陷有关，例如埃默里-德莱福斯肌营养不良症（EDMD）。虽然导致这些疾病的基因突变是已知的，其分子机制核膜扰动导致疾病的原因仍不清楚。此外，目前还不清楚为什么普遍表达的核膜蛋白的突变导致组织特异性发病机制，例如横纹肌特异性缺陷。我们的实验室最近表明核膜跨膜蛋白 39 (NET39) 是核膜结构和功能的肌肉特异性调节剂。 NET39 下调 EDMD 患者肌肉活检，小鼠 Net39 缺失导致核膜变形，先天性肌病和青少年致死率。在核膜内，NET39 与核膜的多个组件相互作用。核膜，例如 LEMD2。我们对 NET39 的研究提供了一个切入点来解开长期存在的问题为什么横纹肌在核膜相关疾病中受到特别影响的谜题。我们假设 NET39 在 EDMD 的发病机制中发挥着关键的骨骼肌特异性作用。本项目的总体目标的目的是定义 NET39 的功能及其与其他核膜蛋白在调节核中的相互作用。骨骼肌稳态和疾病期间的包膜完整性和基因表达，并探讨其作用 NET39 在 EDMD 和其他核纤层蛋白病中的作用。最终，我们希望利用这些见解来开发新的 EDMD 和相关核纤层蛋白病的治疗策略。