Homeostatic regulation of endothelial mechanotransduction

内皮机械传导的稳态调节

• 批准号: 10877241
• 负责人: Brian Gene Coon
• 金额: $ 29.37万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10877241
• 关键词: Binding; Blood Vessels; Blood flow; Cells; Complex; Coupling; Cues; DNA Sequence Alteration; Data; Defect; Elements; Endothelial Cells; Endothelium; GLMN gene; GTF2H1 gene; Genes; Genetic; Genetic Transcription; Homeostasis; Inflammation; Inflammatory; Knock-out; Liquid substance; MADH2 gene; MAP Kinase Gene; MAPK7 gene; MEKKs; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; NF-kappa B; Names; Oklahoma; Pathology; Pathway interactions; Phosphotransferases; Polyubiquitin; Proteins; Regulation; Research; Role; Scaffolding Protein; Signal Transduction; Source; Testing; Ubiquitin; Vascular Diseases; Vascular Endothelium; biological adaptation to stress; body system; design; experimental study; in vivo; insight; malformation; mechanotransduction; mitochondrial dysfunction; mutant; proteotoxicity; reconstitution; response; shear stress; transcription factor; ubiquitin-protein ligase

The vascular endothelium's principal responsibility is to support the inflammatory and metabolic needs of each of the body's organ systems. As such, these cells are highly sensitive to environmental cues and must be able to respond in a precise manner. The regulation of these responses likely occurs via numerous competing pathways. Of particular importance are the fluid shear stress forces imparted by blood flow. The mechanosensitive transcription factors KLF2 and KLF4 compete with other mechanosensitive transcription factors such as NF-kB and SMAD2/3 to suppress inflammation and vessel remodeling. Defects in the coupling between these competing pathways can cause vascular malformations. Klf2/4 are transcriptionally regulated by a MAPK-complex consisting of the kinases MEKK2/3, MEK5, and ERK5, and the scaffold protein p62. Importantly, the p62-MAPK-Klf2/4 axis is activated by high shear but suppressed by low shear to permit low shear-induced inflammation and remodeling. Besides the MAPKs, p62 also interacts with mitochondrial proteins and polyubiquitinated proteins. As mitochondrial remodeling and proteotoxic stress responses have been implicated in both shear responses and p62 signaling, this project will explore the possibility that shear-dependent changes to mitochondrial or ubiquitin homeostasis acts as a key regulator of p62-MAPK signaling. In aim 1 we will test shear-dependent changes to mitochondrial function and the role of mitochondria in regulating p62-MAPK-Klf2/4 signaling. In aim 2 we characterize shear-dependent changes to the ubiquitinome, determine its role in regulating p62-MAPK-Klf2/4 signaling, and the role of ubiquitin homeostasis regulating crosstalk between mechanotransduction pathways. The results obtained in this project will provide insight into the regulation of homeostatic mechanotransduction pathways and may reveal genetic and environmental drivers of KLF2-4-associated pathologies.

血管内皮的主要职责是支持炎症和代谢， 身体各器官系统的需求。因此，这些细胞对 环境提示，必须能够以精确的方式做出反应。这些规则 反应可能通过许多竞争途径发生。特别重要的是流体 血流产生的剪切应力。机械敏感性转录因子KLF 2和 KLF 4与其他机械敏感性转录因子如NF-κ B和SMAD 2/3竞争， 抑制炎症和血管重塑。这些相互竞争的产品之间的耦合缺陷 会导致血管畸形Klf 2/4受MAPK复合物的转录调控 由激酶MEKK 2/3、MEK 5和ERK 5以及支架蛋白p62组成。重要的是 p62-MAPK-Klf 2/4轴被高剪切激活，但被低剪切抑制，以允许低剪切。 剪切引起的炎症和重塑。除了MAPKs，p62还与线粒体 蛋白质和多聚泛素化蛋白质。由于线粒体重塑和蛋白毒性应激 剪切反应和p62信号传导都涉及到了这种反应，本项目将探讨 线粒体或泛素稳态的剪切依赖性变化可能是 p62-MAPK信号转导的关键调节因子。在aim 1中，我们将测试线粒体的剪切依赖性变化， 线粒体的功能和作用 p62-MAPK-Klf 2/4信号转导。在目标2中，我们描述了剪切依赖的泛素化改变， 确定其在调节p62-MAPK-Klf 2/4信号传导中的作用，以及泛素稳态的作用。 调节机械转导通路之间的串扰。本项目取得的成果 将提供对稳态机械转导通路调节的深入了解，并可能揭示 KLF 2 -4相关病理的遗传和环境驱动因素。