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ECM stiffness, mechanotransduction, and cell cycling

ECM 硬度、力转导和细胞循环

基本信息

批准号：
10210426
负责人：
Richard Assoian
金额：
$ 42.49万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210426
关键词：
Abbreviations Address Adhesions Affect Age Area Arteries Atomic Force Microscopy BCAR1 gene Biological Biological Models Cardiovascular Diseases Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Proliferation Cells Complement Connective Tissue Cues Cyclin D1 Cyclin-Dependent Kinases Cyclins Data Embryo Event Extracellular Matrix Extracellular Matrix Proteins Family Fibroblasts Fibronectins Fibrosis Fluorescent in Situ Hybridization Focal Adhesion Kinase 1 G1 Phase Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Histology Hydrogels Immunoprecipitation In Vitro Injury Integrins Lead Liver Fibrosis MALAT1 gene MYH11 gene Malignant Neoplasms Mechanics Mediating Molecular Molecular Analysis Mus Pathology Pathway Analysis Physiology Proliferating Protein-Lysine 6-Oxidase Proteins Pulmonary Fibrosis Regulation Repression Research S Phase Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Specificity Surface Tamoxifen Testing Tissue Model Tissues Tunica Adventitia Untranslated RNA Vascular Smooth Muscle Western Blotting arterial stiffness base experimental study extracellular in vivo inhibitor/antagonist interest kinase inhibitor locked nucleic acid mechanotransduction mouse model myocardin novel paxillin prevent programs response rho transcription factor transcriptome sequencing vascular injury

项目摘要

SUMMARY Mechanobiology--how cells and tissues sense and respond to mechanical influences--is a rapidly growing field of increasing importance to the understanding of physiology and fibrosis-associated pathologies including cancer, lung and liver fibrosis, and especially cardiovascular disease. This application studies how cells sense and respond to mechanical cues contained within the stiffness of the extracellular matrix (ECM). Mechanical information in the ECM is relayed through integrin-adhesions and Rho family GTPases, but how these early signaling events drive cell fate and function remains poorly understood. Unraveling these connections is a major challenge in the field. We are addressing this gap in understanding by examining how changes in ECM stiffness are transduced into the signaling events that control cell cycling. By combining molecular analyses with cell culture on deformable substrata (hydrogels), we recently showed that focal adhesion kinase (FAK), p130Cas, and Rac comprise a discrete signaling module that functions as a positive regulator of stiffness-sensitive cyclin D1 expression and cell cycling into S phase. But signaling in non- transformed cells is rarely linear and uni-directional: negative regulation commonly complements positive signaling to provide tight control of fate. These negative signals and pathways are often not well understood, and this is certainly the case for stiffness-regulated mechanotransduction. We therefore used RNASeq to search for ways that cells might limit stiffness-sensing to prevent over-stimulation. This analysis identified the long noncoding RNA, MALAT1, as a novel negative regulator of stiffness-dependent cell cycling: MALAT1 stimulates entry into S phase, but ECM stiffness reduces the expression level of MALAT1. Curiously, stiffness- stimulated Rac activity mediates both the induction of cyclin D1 and the repression of MALAT1. We now propose to examine the relationships between ECM stiffness, MALAT1 and cyclin D1, and their upstream activators. Aim 1 will examine the impact of MALAT1 on the G1 phase cyclin-cdks, assess crosstalk between MALAT1 and cyclin D1, and determine how changes in ECM composition and integrin display may affect rigidity-dependent regulation of MALAT1, cyclin D1 and cell cycling. Aim 2 looks upstream of cyclin D1 and MALAT1 and will determine how distinct components in the integrin-adhesion that share an ability to activate Rac can differentially regulate MALAT1. Finally, Aim 3 will test the relevance of our findings in vivo by analyzing smooth muscle cell proliferation in a mouse model of tissue stiffening and smooth muscle cell proliferation after vascular injury.

总结