Biophysical regulation of macrophage function

巨噬细胞功能的生物物理调节

• 批准号: 10268232
• 负责人: Wendy Liu
• 金额: $ 57.87万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268232
• 关键词: Actins; Adhesions; Biochemical; Biocompatible Materials; Biophysics; Calcium; Cardiovascular Diseases; Cell Proliferation; Cell Shape; Cells; Cues; Cytoskeletal Modeling; Cytoskeleton; Data; Disease; Engineering; Environment; Extracellular Matrix; Fibrosis; Functional disorder; Genetic; Genetic Transcription; Goals; Homeostasis; Hydrogels; Imaging Device; Immune response; Implant; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Ion Channel; Knowledge; Lead; Leucocytic infiltrate; Macrophage Activation; Malignant Neoplasms; Measures; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Nuclear; Nuclear Protein; Organ Size; Permeability; Pharmacology; Phenotype; Piezo 1 ion channel; Population; Process; Proteins; Regulation; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Protein; Solid; Stimulus; Testing; Tissues; Work; biophysical properties; capsule; chemokine; chronic inflammatory disease; cytokine; healing; imaging approach; immune function; immunomodulatory strategy; implant material; improved; in vivo; macrophage; monocyte; mouse model; new therapeutic target; novel; pathogen; polymerization; protein expression; response; single-cell RNA sequencing; spatiotemporal; subcutaneous; tissue repair; tool; wound healing

PROJECT SUMMARY Macrophages are central regulators of inflammation and tissue healing following injury or infection, and during disease. While much is known about how soluble, biochemical factors in the environment regulate macrophage function, less is known about how biophysical cues regulate their response, despite the fact that these cells exist within solid tissues that are rich in mechanical cues. Furthermore, many diseases in which macrophages are involved, such as cancer and fibrosis, are characterized by changes in tissue biophysical properties. Our previous work demonstrated that adhesion to soft extracellular matrix hydrogels inhibits macrophage inflammatory activation. In preliminary work, we found that matrix rigidity influences the localization of YAP, a transcriptional co-factor involved in cell proliferation, organ size control, and cancer, but with previously undescribed role in macrophage activation. Adhesion to stiff substrates leads to YAP nuclear localization, which appears to prime macrophages for a potent inflammatory response. In addition, cytoskeletal polymerization and the mechanically-activated and calcium-permeable ion channel Piezo1 appear to be involved in YAP nuclear localization and inflammatory activation. In this study, we propose to investigate the molecular mechanisms underlying YAP signaling and Piezo1 activity in the macrophage response within different stiffness environments. In Aim 1, we will examine the effect of stiffness on cytoskeletal remodeling and associated signaling pathways on YAP activity. In Aim 2, we will probe the role of Piezo1-mediated calcium activity in stiffness sensing, YAP signaling, and macrophage function. Finally, in Aim 3, we will investigate the role of YAP and Piezo1 on macrophage-mediated wound healing in vivo using a murine subcutaneous biomaterial implant model. An improved fundamental understanding of how macrophages sense their mechanical environment may lead to new immunomodulatory strategies that control macrophage function during disease.

项目摘要 巨噬细胞是受伤后炎症和组织愈合的中心调节剂 感染和疾病。虽然对如何可溶于生化因素是众所周知的 环境调节巨噬细胞函数，对生物物理提示如何调节 尽管这些细胞存在于富含机械的固体组织中，但它们的反应 提示。此外，涉及巨噬细胞的许多疾病，例如癌症和 纤维化的特征是组织生物物理特性的变化。我们以前的工作 证明对软细胞外基质水凝胶的粘附抑制了巨噬细胞 炎症激活。在初步工作中，我们发现矩阵刚度会影响 YAP的定位，涉及细胞增殖，器官大小控制和 癌症，但在巨噬细胞激活中具有先前未描述的作用。粘附到僵硬 底物导致YAP核定位，这似乎是巨噬细胞的质量 炎症反应。另外，细胞骨架聚合和机械激活 钙可渗透的离子通道压电1似乎参与YAP核定位和 炎症激活。在这项研究中，我们建议研究分子机制 巨噬细胞响应中不同刚度内的基础YAP信号传导和压电活性 环境。在AIM 1中，我们将检查刚度对细胞骨架重塑的影响和 相关的信号通路在YAP活动上。在AIM 2中，我们将探测Piezo1介导的作用 刚度传感，YAP信号传导和巨噬细胞功能中的钙活性。最后，在AIM 3中 我们将研究YAP和Piezo1在体内巨噬细胞介导的伤口愈合中的作用 使用鼠皮下生物材料植入物模型。改进的基本 了解巨噬细胞如何感知其机械环境可能导致新的 在疾病期间控制巨噬细胞功能的免疫调节策略。