Identification and Characterization of an Integrin - Notch Signaling Axis

整合素 -Notch 信号轴的鉴定和表征

• 批准号: 9231986
• 负责人: Allan R Albig
• 金额: $ 41.36万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231986
• 关键词: Address; Behavior; Belief; Binding; Biological; Biology; Blood Vessels; Cell Communication; Cell physiology; Cells; Cellular biology; Communication; Complex; Couples; Data; Disease; Endothelial Cells; Environment; Event; Exposure to; Extracellular Matrix; Fibrosis; Genetic Transcription; Goals; Habitats; Half-Life; Human Pathology; Individual; Integrins; Investigation; Laboratories; Ligands; Link; Manuscripts; Mediating; Membrane; Molecular; Mutation; Normal Range; Notch Signaling Pathway; Nuclear Envelope; Organism; Parents; Pathologic; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Post-Translational Protein Processing; Process; Proteins; Publishing; Research; Research Personnel; Role; Science; Signal Transduction; Site; Students; System; Technology; Tissues; Training; Tyrosine Phosphorylation; Vascular System; base; career; experimental study; gamma secretase; graduate student; high school; human disease; notch protein; novel; parent grant; promoter; response; shear stress; skills; src-Family Kinases; transcription factor; undergraduate student

Project Summary Collectively, extracellular matrix, integrins, and Notch regulate a host of normal and pathological cellular activities. Evidence emerging from our preliminary studies shows that these cellular entities are coordinated into a signaling mechanism that has not been previously observed. The implications of our observation are broad and likely to have deep impacts on our understanding of cell interactions with cellular microenvironments as well as cellular behaviors in a range of normal and pathological scenarios. In this renewal application, the main objectives are to fill in the gaps of our current understanding of the molecular mechanism by which integrins regulate Notch and to explore the importance of this novel signaling system to several aspects of endothelial cellular function. To investigate the molecular mechanism in aim 1, we will focus on understanding how downstream integrin signaling through Src kinase impacts Notch activity. We will specifically focus on understanding how Src kinase controls 1a) the half-life of active N1ICD fragments, 1b) transcriptional activity of N1ICD, and 1c) the N1ICD transcription factor complex. In aim 2 we will determine if this signaling system is operant in a variety of endothelial functions including 2a) response to non-canonical β3 ligands, 2b) response to matrix stiffness, and 2c) response to shear stress. Given that each of these important endothelial functions are known to be individually influenced by extracellular matrix, integrin activity, and Notch signaling, we hypothesize that these endothelial functions will also be dependent on coordinated activity between these signaling mechanisms. Throughout these studies, we will engage high school, undergraduate, and graduate students to collectively build scientific confidence and teach skills these students will require in order to pursue careers in science. At the conclusion of our studies, we will have accomplished two important milestones towards understanding this novel regulatory mechanism. Specifically, we will have unraveled many molecular details describing how integrins control Notch, and we will have defined the importance of this signaling cascade to basic endothelial cell functions which when aberrant, are associated with a significant number of human pathologies.

项目总结