Imaging the early events in membrane receptor signaling

对膜受体信号传导的早期事件进行成像

• 批准号: 10004156
• 负责人: Diane Lidke
• 金额: $ 42.02万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004156
• 关键词: Behavior; Biochemical; Biological Process; Biology; Biophysics; Cell Surface Receptors; Cell model; Cell physiology; Cells; Disease; Event; Fostering; Goals; Growth Factor Receptors; Hypersensitivity; Image; Imaging Techniques; Ligand Binding; Malignant Neoplasms; Measures; Membrane; Methods; Microscopy; Mission; Molecular; Outcome; Protein Dynamics; Protein Tyrosine Kinase; Proteins; Public Health; Receptor Signaling; Research; Shapes; Signal Transduction; Techniques; United States National Institutes of Health; innovation; population based; programs; protein protein interaction; receptor; response; spatiotemporal; tool

Project Summary Understanding the molecular mechanisms that shape an effective cellular response is a fundamental question in biology. While much is known about the chain of events initiated by membrane receptor-ligand binding, there is a fundamental gap in our understanding of how protein dynamics facilitate signaling. The long-term goal of my research program is to understand how the dynamic and stochastic behavior of protein-protein interactions is integrated to produce an efficient signaling response. The objective of this proposal is to quantify protein dynamics during the early events of membrane-associated signaling. Our central hypothesis is that the duration of protein-protein interactions modulates the signaling outcome. The rationale for the proposed research is that in order to understand signal transduction, it is critical to determine the sequence, lifetime and sub-cellular localization of biochemical events that initiate signaling. We use unique and innovative imaging techniques to provide quantitative information on the dynamics of early signaling events that cannot be obtained using traditional biochemical (population-based) techniques. We will apply our unique tool box, including state-of-the-art microscopy methods, biophysical and functional read-outs, in an integrated approach to provide a comprehensive picture of how protein-protein dynamics regulate tyrosine kinase signaling downstream of growth factor receptors and immunoreceptors. The proposed research is significant because the quantitative information that we will obtain has not been directly measured before and will bring new perspectives to cell biological processes, both in normal and disease states. By connecting the activation state of cell surface receptors with their dynamics, signaling partner interplay and downstream signaling events, we will are filling in critical spatiotemporal gaps in our models of cell signaling.

项目概要 了解形成有效细胞反应的分子机制是一个关键 生物学中的基本问题。尽管人们对由 膜受体-配体结合，我们对如何结合的理解存在根本差距 蛋白质动力学促进信号传导。我的研究计划的长期目标是 了解蛋白质-蛋白质相互作用的动态和随机行为是如何整合的 产生有效的信号响应。该提案的目的是量化蛋白质 膜相关信号传导早期事件的动力学。我们的中心假设是 蛋白质-蛋白质相互作用的持续时间调节信号传导结果。理由 对于拟议的研究来说，为了理解信号转导，至关重要的是 确定启动的生化事件的序列、寿命和亚细胞定位 发信号。我们使用独特和创新的成像技术来提供定量信息 关于无法使用传统生化方法获得的早期信号事件的动态 （基于人群的）技术。我们将应用我们独特的工具箱，包括最先进的 显微镜方法、生物物理和功能读数，以综合方法提供 蛋白质-蛋白质动力学如何调节酪氨酸激酶信号传导的全面图景 生长因子受体和免疫受体的下游。拟议的研究是 重要的是因为我们将获得的定量信息尚未直接 以前测量过的，将为正常情况下的细胞生物过程带来新的视角 和疾病状态。通过将细胞表面受体的激活状态与其 动态、信号合作伙伴相互作用和下游信号事件，我们将填写 我们的细胞信号传导模型中的关键时空差距。