RECEPTOR AGGREGATION AND ITS EFFECTS

受体聚集及其影响

• 批准号: 2177960
• 负责人: BYRON B GOLDSTEIN
• 金额: $ 14.21万
• 依托单位: UNIVERSITY OF CALIF-LOS ALAMOS NAT LAB
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2177960
• 关键词: T lymphocyte; antibody receptor; antigen receptors; calcium flux; crosslink; cytokine receptors; cytoskeleton; haptens; immunoglobulin E; interleukin 2; intermolecular interaction; intracellular transport; mathematical model; model design /development; protein transport; receptor binding

Receptors diffusing over the surface of a cell allow it to sense its environment and respond to it. Often the aggregation of these receptors is crucial to the triggering of cellular responses. We focus on three types of cell surface receptor aggregation, induced by three types of ligands (antigens, antibodies and lymphokines) that play important roles in the immune response. 1. Antigens aggregate cell surface immunoglobulin (sIg) and in the process initiate responses in B lymphocytes, basophils and mast cells. 2. Anti-sIg solution antibodies (IgG) span sIg and Fcgamma receptors and on B lymphocytes these co-crosslinks inhibit signals generated by aggregated sIg. 3. Interleukin 2 (IL-2), induces the aggregation of IL-2 receptors on activated T cells generating signals that lead to the control of T cell growth and IL-2 secretion. Our aim is to understand to develop mathematical models that can predict the time course of such aggregate formation, and to relate this aggregation to specific cellular responses. The role of the mathematical models is to help devise rigorous test of ideas about the system, aid in analyzing experiments, determine parameter values, and suggest new experiments. We use rat basophilic leukemia (RBL) cells sensitized with monoclonal anti- hapten IgE as a model system for studying general features of receptor aggregation as well as specific effects of sIg aggregation and sIg-FcgammaR co-crosslinking. The formation of IgE aggregates on RBL cells triggers numerous cellular responses, but not all aggregates trigger all responses. To determine what properties are required of an IgE aggregate to make it an effective initiator of a particular response we will fully characterize the binding properties of haptens of different lengths, flexibilities and valence so that we can predict how the distribution of hapten-IgE with the responses of the RBL cell surfaces. We then will compare these predictions with the responses of the RBL cell (Ca2+ fluxes, degranulation, cytoskeletal interactions, IgE internalization), to relate surface aggregates to cellular responses. We also will use the RBL system to study the initial events (and how to block them) that occur when a large antigen or virion attaches to a cell surface. In building a mathematical model of the interaction of IL-2 with its surface receptors, we focus on experiments using T cell clones expressing different concentrations of light and heavy chain receptors. The studies in this project are health related, bearing on allergic reactions and their treatment, normal and abnormal T cell growth, and other aspects of the immune response.

受体在细胞表面上扩散，使其感知其 环境并回应它。 这些受体的聚集通常是 对于触发细胞反应至关重要。 我们专注于三种类型 细胞表面受体聚集，由三种类型的配体诱导 （抗原，抗体和淋巴细胞）在 免疫反应。 1。抗原聚集细胞表面免疫球蛋白（SIG） 在此过程中 细胞。 2。抗SIG溶液抗体（IgG）Span Sig和Fcgamma 受体和B淋巴细胞上这些共链链接抑制信号 由汇总SIG生成。 3。白介素2（IL-2），诱导 IL-2受体在激活的T细胞上产生信号的聚集 导致控制T细胞生长和IL-2分泌。 我们的目标是 了解要开发可以预测时间课程的数学模型 这种骨料形成，并将这种汇总与特定 细胞反应。 数学模型的作用是帮助设计 严格测试有关该系统的想法，有助于分析实验， 确定参数值，并建议新的实验。 我们使用大鼠嗜碱性白血病（RBL）细胞，与单克隆抗 - Hapten IgE作为研究受体一般特征的模型系统 SIG聚集和SIG-FCAMMAR的聚集以及特定效果 共链接。 RBL细胞上的IgE聚集物的形成触发 许多细胞响应，但并非全部聚集物触发所有反应。 确定IgE骨料需要哪些属性才能使其成为 特定响应的有效发起者我们将充分表征 不同长度，灵活性和 价，以便我们可以预测触觉的分布如何与 RBL细胞表面的响应。 然后，我们将比较这些预测 随着RBL细胞的响应（Ca2+通量，脱粒， 细胞骨架相互作用，IgE内在化），以相关表面 骨料对细胞反应。 我们还将使用RBL系统学习 大抗原时发生的初始事件（以及如何阻止它们） 或病毒体附着在细胞表面上。 在建立一个数学模型 IL-2与其表面受体的相互作用，我们专注于实验 使用表达不同浓度的光和沉重的T细胞克隆 链受体。 该项目的研究与健康有关， 关于过敏反应及其治疗，正常和异常T细胞 生长和免疫反应的其他方面。