Quantitative Methods for Studying Cell Signaling Mediated by Multisubunit Immuno-receptors

[9723897] Wofsy数学和统计学方法，结合两个细胞生物学实验室的实验工作，将用于阐明细胞外信号分子与细胞表面特定受体相互作用时发生的早期生物物理和生化事件，以启动和调节细胞反应。在过去的十年中，大量的实验工作揭示了不同生理系统中细胞信号传导的共同特征。一般来说，细胞外信号分子诱导细胞表面受体聚集，对于许多受体来说，第一个可检测到的细胞对受体聚集的反应是受体和其他细胞蛋白上氨基酸酪氨酸的磷酸化。然后细胞内酶与新磷酸化位点相互作用并介导进一步的生化和细胞反应。提出的工作试图澄清信号级联的初始事件：受体聚集和酪氨酸磷酸化，对于免疫系统的多亚单位受体。部分工作涉及分析新获得的细胞表面图像上的点模式，反映细胞表面受体的空间分布。该项目继续合作，旨在利用这些图像定量地推断受体聚集的机制和影响。此外，还将开发和应用点模式分析的其他统计方法，以了解不同聚集状态与细胞反应之间的关系。第二个合作解决机制，通过聚集受体介导酪氨酸磷酸化受体和其他底物。这些研究将为细胞信号传导早期事件的机制提供模型，这将导致能够测试它们的实验。许多细胞表面受体通过聚集对配体结合作出反应，随后受体和其他细胞蛋白中的酪氨酸残基发生磷酸化。这里的研究将使用实验系统的数学建模来澄清免疫系统受体信号级联中的这些初始事件。＊＊＊

9723897 Wofsy Methods of mathematics and statistics, in conjunction with experimental work in two cell biology laboratories, will be used to clarify the early biophysical and biochemical events that occur when extracellular signaling molecules interact with specific receptors on cell surfaces, to initiate and regulate cellular responses. Common features of cell signaling in different physiological systems have emerged from intensive experimental work over the past decade. In general, the extracellular signaling molecules induce the aggregation of cell surface receptors, and for many receptors, the first detectable cellular response to receptor aggregation is the phosphorylation of the amino acid tyrosine on the receptor and other cellular proteins. Intracellular enzymes then interact with the newly phosphorylated sites and mediate further biochemical and cellular responses. The proposed work attempts to clarify the initial events in the signaling cascade: receptor aggregation and tyrosine phsophorylation, for the multi-subunit receptors of the immune system. Part of the work involves analysis of point patterns on newly available cell surface images, reflecting the spatial distribution of cell surface receptors. This project continues a collaboration designed to use such images quantitatively to make inferences about the mechanisms and effects of receptor aggregation. The development and application of additional statistical methods of point pattern analysis to understand the relationship between different aggregation states and cellular responses will also be done. The second collaboration addresses mechanisms by which aggregated receptors mediate the phosphorylation of tyrosine on receptors and other substrates. These studies will provide models for the mechanisms of the early events in cell signaling, which should lead to experiments that can test them. %%% A number of cell surface receptors respond to ligand binding by aggregation, which is then followed by phospho rylation of tyrosine residues in the receptor and other cellular proteins. The research here will use mathematical modeling of experimental systems to clarify these initial events in the signaling cascade for receptors of the immune system. ***