Investigating tyrosine phosphorylation of Notch proteins

项目摘要 细胞外基质、整合素和Notch共同调节一系列正常和病理的 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 细胞微环境中的细胞相互作用以及在一系列 正常和病态的场景。在这个续订申请中，我们调查了假设 Notch酪氨酸磷酸化调控血管生成。为了解决这一假设，我们 我提出了两个目标，即通过以下途径更深入地挖掘Notch活性的分子调控 Src激酶对酪氨酸的磷酸化作用，以及Notch酪氨酸磷酸化的机制 影响血管生成和血管功能。在这些研究中，本着 区域计划，我们将吸引高中、本科生和研究生来建设 这些学生需要科学自信和传授技能，以便在 科学。在我们的研究结束时，我们将完成两个重要里程碑 有助于理解这一新颖的调控机制。具体地说，我们将解开 描述了Src如何控制Notch的许多分子细节，我们将定义 这一信号级联对血管生物学的重要性。由于Notch和血管生物学 在各种正常和疾病状态下运行，我们的工作与 促进人类健康。

Project Summary Extracellular matrix, integrins, and Notch collectively 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 within cellular microenvironments as well as cellular behaviors in a range of normal and pathological scenarios. In this renewal application, we investigate the hypothesis that Notch tyrosine phosphorylation regulates angiogenesis. To address this hypothesis, we have proposed two aims that dig deeper into the molecular regulation of Notch activity through tyrosine phosphorylation by Src kinase, and to understand how Notch tyrosine phosphorylation impacts angiogenesis and vascular function. Throughout these studies and in the spirit of the AREA program, we will engage high school, undergraduate, and graduate students to 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 Src controls Notch, and we will have defined the importance of this signaling cascade to vascular biology. Since both Notch and vascular biology operate in a wide variety of normal and disease states, our work is highly relevant to the promotion of human health.