Signal Integration during Phagocytosis

吞噬过程中的信号整合

• 批准号: 10655648
• 负责人: Meghan A Morrissey
• 金额: $ 37.9万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655648
• 关键词: Affect; Binding; Biochemical; Biophysical Process; Cell Survival; Cells; Data; Disease; Dose; Eating; Environment; Fc Receptor; Foundations; Future; Goals; Immunoglobulin G; Inflammation; Ligands; MAPK Signaling Pathway Pathway; Macrophage; Measures; Molecular; NF-kappa B; Output; Pattern; Phagocytosis; Reaction; Signal Pathway; Signal Transduction; Stimulus; density; pathogen; rapid detection; receptor; response

Morrissey Project Summary: (30 lines) The long-term goal of this project is to understand how cells control their sensitivity to external stimuli. Macrophages are a particularly interesting example of this because they constantly encounter background stimuli, like IgG, in their surrounding environment. Macrophage signaling pathways are carefully tuned to rapidly detect IgG-bound pathogens without reacting to healthy cells. Macrophages respond to IgG by activating phagocytosis and/or inflammation. The short-term goal of this project is to define how macrophages set a response threshold for these outputs. We are approaching this problem from two directions. The first direction is examining how receptor clustering or co-clustering affects macrophage sensitivity. Our previous data shows that clustering of activating ligands enhances activation of the Fc Receptor, and increases phagocytosis. Phagocytosis is also controlled by inhibitory ‘Don’t eat me’ signals on viable cells. We are now expanding our studies to examine how clustering of inhibitory ligands, and co-clustering of inhibitory and activating ligands affects phagocytosis. This will suggest how ligand or receptor pattern can tune macrophage sensitivity. Our second direction is examining the intracellular signaling that filters out sub-threshold stimuli. Our preliminary data suggests that a higher IgG signal is required for inflammation than phagocytosis. We will address the following questions: What parameter do macrophages measure to determine IgG signal intensity – signal duration, IgG density, or total number of IgG molecules? What is the molecular breakpoint in the IgG signaling pathway that is only activated by high IgG? How does IgG stimulus intensity affect signaling dynamics in the NFkB and MAPK signaling pathways? Overall, this will suggest how macrophages are able generate two separate responses from a single input based on dose.

莫里西 项目摘要：（30行） 这个项目的长期目标是了解细胞如何控制它们对外部刺激的敏感性。 宏程序是一个特别有趣的例子，因为它们经常遇到背景 刺激物，如IgG，在其周围环境中。巨噬细胞信号通路被仔细调整， 快速检测IgG结合的病原体，而不会对健康细胞产生反应。巨噬细胞对IgG的反应是 激活吞噬作用和/或炎症。这个项目的短期目标是确定巨噬细胞如何 为这些输出设置响应阈值。我们正从两个方向来处理这个问题。第一 方向是研究受体聚集或共聚集如何影响巨噬细胞的敏感性。我们以前的 数据显示活化配体的聚集增强Fc受体的活化， 吞噬作用吞噬作用也由活细胞上的抑制性“不要吃我”信号控制。我们现在 扩大我们的研究，以研究抑制性配体的聚类，以及抑制性和 激活配体影响吞噬作用。这将提示配体或受体模式如何调节巨噬细胞 灵敏度我们的第二个方向是检查细胞内信号，过滤出亚阈值刺激。 我们的初步数据表明，炎症比吞噬作用需要更高的IgG信号。我们将 解决以下问题：巨噬细胞测量什么参数来确定IgG信号强度- 信号持续时间、IgG密度或IgG分子总数？IgG中的分子断裂点是什么 仅由高IgG激活的信号通路？IgG刺激强度如何影响信号传导 NFkB和MAPK信号通路的动力学？总的来说，这将表明巨噬细胞如何能够 基于剂量从单个输入生成两个单独的响应。