Nucleocytoplasmic Transport in Skeletal Muscle

骨骼肌中的核细胞质转运

基本信息

批准号：
8531864
负责人：
Grace K Pavlath
金额：
$ 32.96万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531864
关键词：
Affect Age Aging Biological Assay Breathing Carrier Proteins Cell Count Cell Nucleus Cell Proliferation Cell physiology Cells Confocal Microscopy Cytoplasm Data Dextrans Disease Enzymes Eukaryota Gene Expression Genes Goals Growth Homeostasis In Vitro Individual Injury Knockout Mice Label Lead Literature Locomotion Longevity Mediating Metabolism Mitosis Mitotic Molecular Weight Mus Muscle Muscle Cells Muscle Fibers Muscle function Myoblasts Natural regeneration Nuclear Nuclear Export Nuclear Import Nuclear Pore Nuclear Pore Complex Nuclear Proteins Oxidative Stress Pathway interactions Physiological Physiology Pore Proteins Protein Binding Proteins Publishing Regulation Repression Role Signal Transduction Skeletal Muscle Stem cells Stress Testing Therapeutic Tissues Translating Variant aged base cell motility chromatin remodeling dextran gene repression genetic regulatory protein in vivo insight muscle aging muscle form muscle regeneration normal aging nuclear reprogramming nucleocytoplasmic transport oxidative damage prevent protein transport receptor repaired research study response satellite cell transcription factor

项目摘要

DESCRIPTION (provided by applicant): Proper skeletal muscle function is dependent on activation and repression of numerous genes in satellite cells, which are tissue-specific stem cells, as well as in multinucleated contractile myofibers. Gene expression is regulated in part by controlling the localization of proteins with nuclear functions, such as transcription factors and chromatin remodeling enzymes. The subcellular localization of these nuclear proteins must be tightly controlled because altered nuclear import or export could result in aberrant muscle mass and function. How key nuclear regulatory proteins gain access to nuclei in satellite cells and myofibers is unknown. Most transport between the nucleus and the cytoplasm is mediated by nuclear pore complexes in concert with nuclear transport receptors that recognize cargo proteins and mediate transport through these nuclear pores. Our long-term goal is to understand the function of the nuclear transport machinery in normal and aged muscle and how it contributes to control of gene expression. Based on our preliminary data together with published literature, we hypothesize that perturbations in the nuclear transport machinery (nuclear import receptors and nuclear pores) alter muscle physiology. This proposal uses complementary in vitro and in vivo approaches to probe different components of the nucleocytoplasmic transport machinery in satellite cells and myofibers in order to obtain an integrated analysis of nuclear transport. Thus, we will interrogate the function of specific nuclea import receptors in satellite cells (Aim 1) and the selectivity of specific nuclear import pathways for individual nuclei of multinucleated myofibers (Aim 2). In addition, we will assess nuclear pore selectivity in skeletal muscle nuclei in response to aging and oxidative stress (Aim 3). Understanding how nucleocytoplasmic transport is regulated in skeletal muscle will lead to a greater understanding of how external signals are sensed by muscle cells and translated into changes in gene expression necessary for tissue homeostasis. These analyses may provide new targets for preventing loss of muscle mass with aging, injury, or disease. In addition, our analyses may enhance the efficiency of cell therapeutic approaches that rely on fusion and nuclear reprogramming of individual donor cells with multinucleated myofibers.

描述（由申请人提供）：适当的骨骼肌功能取决于卫星细胞（组织特异性干细胞）以及多核收缩肌纤维中众多基因的激活和抑制。基因表达在一定程度上是通过控制具有核功能的蛋白质（例如转录因子和染色质重塑酶）的定位来调节的。这些核蛋白的亚细胞定位必须受到严格控制，因为核输入或输出的改变可能导致肌肉质量和功能异常。关键的核调节蛋白如何进入卫星细胞和肌纤维的细胞核尚不清楚。细胞核和细胞质之间的大多数转运是由核孔复合物与核转运受体介导的，核转运受体识别货物蛋白并介导通过这些核孔的转运。我们的长期目标是了解正常和衰老肌肉中核转运机制的功能以及它如何有助于控制基因表达。根据我们的初步数据和已发表的文献，我们假设核运输机制（核输入受体和核孔）的扰动会改变肌肉生理学。该提案使用互补的体外和体内方法来探测卫星细胞和肌纤维中核细胞质运输机制的不同组成部分，以获得核运输的综合分析。因此，我们将探讨卫星细胞中特定核输入受体的功能（目标 1）以及特定核输入途径的选择性对于多核肌纤维的单个核（目标 2）。此外，我们将评估核孔骨骼肌细胞核对衰老和氧化应激的选择性反应（目标 3）。了解骨骼肌中核细胞质运输的调节方式将有助于更好地了解肌肉细胞如何感知外部信号并转化为组织稳态所需的基因表达的变化。这些分析可能为预防因衰老、受伤或疾病而导致的肌肉质量损失提供新的目标。此外，我们的分析可能会提高细胞治疗方法的效率，这些方法依赖于单个供体细胞与多核肌纤维的融合和核重编程。