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.

项目摘要 总的来说，细胞外基质、整合素和Notch调节许多正常和病理的 细胞活动。从我们的初步研究中出现的证据表明这些细胞 实体被协调成一种以前没有观察到的信号机制。这个 我们观察到的含义是广泛的，可能会对我们的理解产生深刻的影响 细胞与细胞微环境的相互作用以及细胞在一系列 正常和病态的场景。在此续签申请中，主要目标是填写 我们目前对整合素调节分子机制的认识上的差距 并探讨这一新型信令系统对以下几个方面的重要性 内皮细胞功能。为了研究目标1的分子机制，我们将重点研究 了解通过Src激酶的下游整合素信号如何影响Notch活性。 我们将特别关注了解Src激酶是如何控制1)活性半衰期的 N1ICD片段，1b)N1ICD的转录活性，以及1c)N1ICD转录因子 很复杂。在目标2中，我们将确定该信号系统是否在多种内皮细胞中起作用 功能包括2a)对非正则β3配体的反应，2b)对基质刚性的反应， 2c)对剪应力的响应。鉴于这些重要的内皮功能中的每一个 已知分别受细胞外基质、整合素活性和Notch信号的影响， 我们假设，这些内皮功能也将依赖于协调活动 在这些信号机制之间。在这些研究中，我们将让高中学生参与其中， 本科生和研究生集体树立科学信心，传授技能 这些学生将需要在科学方面追求职业生涯。在我们的演讲结束时 通过研究，我们将完成理解这部小说的两个重要里程碑 监管机制。具体地说，我们将解开许多分子细节，描述 整合素如何控制Notch，我们将定义这个信号级联的重要性 对于基本的内皮细胞功能，当这些功能异常时，与大量的 人类的病理性。