Regulation of Cell Cycle progression by the nuclear envelope

核膜对细胞周期进程的调节

基本信息

批准号：
10659597
负责人：
Christophe Daniel Guilluy
金额：
$ 32.67万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
2023-04-10 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659597
关键词：
Acceleration Actomyosin Address Anaphase Biochemical Biophysics Calcium Cardiovascular Diseases Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Nucleus Cell Proliferation Cell physiology Cells Complex Cytoskeleton Disease Event Fibrosis Filament Functional disorder Future G1/S Transition Gene Expression Grant Growth Homeostasis Image Interphase Investigation Malignant Neoplasms Mechanics Mediating Metaphase Mitosis Mitotic spindle Molecular Morphology Normal Cell Nuclear Nuclear Envelope Pathogenesis Pathologic Pathway interactions Physiological Process Proliferating Proteomics S phase Signal Pathway Signal Transduction Stimulus Testing Tissues Transcription Factor AP-1 Up-Regulation Work biophysical tools experience innovation mechanical force mechanotransduction pharmacologic public health relevance response sensor spatiotemporal transcription factor transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT Under physiological conditions, cells are subjected to mechanical tension that triggers multiple signaling pathways and impacts numerous cellular processes, including cell cycle progression. It is well established that a dysfunction of these tension-sensitive signaling pathways can cause unbalanced proliferation and pathological tissue remodeling; however, the precise molecular pathways remain poorly defined. As cells experience tension, the nucleus undergoes significant morphological changes due to its connection with the cytoskeleton that transmits mechanical force to the nuclear envelope. We recently showed that nuclear flattening activates transcription factors that stimulate G1/S transition, leading us to hypothesize that the nuclear membrane could serve as a tension sensor whose activation is necessary for cell cycle progression. Building on these findings, as well as on the work of others, we will test this hypothesis by applying a combination of biophysics, imaging, and biochemical approaches to define the nuclear tension-sensitive pathways that control cell cycle progression. In Aim #1, we will determine whether RhoA-mediated pathways increase actomyosin contractility and nuclear envelope tension during G1 to stimulate G1/S transition. In Aim#2, we will extend our investigation to the signaling triggered in response to an increase in nuclear tension and we will define how these signaling events promote entry into S phase. In Aim#3, we will determine whether tension transmitted to the nucleus during interphase stimulates mitosis progression. We anticipate that the successful completion of this project will increase our understanding of the tension-sensitive mechanisms controlling cell cycle progression and will identify new pharmacological targets to limit cell proliferation in pathological contexts associated with excessive actomyosin tension.

项目概要/摘要在生理条件下，细胞受到机械张力，从而触发多种信号传导途径并影响许多细胞过程，包括细胞周期进程。众所周知这些张力敏感信号通路的功能障碍会导致不平衡的增殖和病理性病变。组织重塑；然而，精确的分子途径仍然不清楚。当细胞经历紧张时，由于细胞核与细胞骨架的连接，细胞核发生显着的形态变化将机械力传递至核膜。我们最近表明核扁平化激活刺激 G1/S 转变的转录因子，使我们推测核膜可以作为张力传感器，其激活对于细胞周期进展是必要的。基于这些发现，以及其他人的工作，我们将通过应用生物物理学、成像、和生化方法来定义控制细胞周期进程的核张力敏感途径。在目标#1中，我们将确定 RhoA 介导的途径是否会增加肌动球蛋白的收缩性和核 G1 期间的包络张力刺激 G1/S 过渡。在目标#2 中，我们将把调查范围扩大到信号传导是为了响应核张力的增加而触发的，我们将定义这些信号传导事件如何促进进入S期。在目标＃3中，我们将确定张力是否在过程中传递到细胞核间期刺激有丝分裂进展。我们预计该项目的顺利完成将增加我们对控制细胞周期进程的张力敏感机制的理解，并将确定新的药理学靶点，以限制与过量相关的病理环境中的细胞增殖肌动球蛋白张力。