Understanding and Controlling Macrophage Behavior in Angiogenesis

了解和控制血管生成中的巨噬细胞行为

• 批准号: 10682565
• 负责人: Kara Lorraine Spiller
• 金额: $ 58.89万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682565
• 关键词: Atherosclerosis; Autoimmune Diseases; Behavior; Biocompatible Materials; Blood Vessels; Brain Ischemia; Cell Therapy; Cell secretion; Complex; Cues; Data; Diabetes Mellitus; Disease; Endothelial Cells; Exhibits; Expression Profiling; Functional disorder; Gene Expression; Goals; Growth; Heart; Hindlimb; Human; Impaired healing; Impairment; In Vitro; Inflammatory; Inflammatory Response; Interleukin 4 Receptor; Interleukin-4; Ischemia; Kinetics; Leukocyte Trafficking; Macrophage; Mediating; Mediator; Modeling; Mus; Myocardial Ischemia; Pathologic Neovascularization; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Process; Regulation; Regulatory T-Lymphocyte; Signal Transduction; Stimulus; Supporting Cell; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Vascularization; Work; angiogenesis; cancer therapy; chronic wound; design; directed differentiation; efficacy testing; healing; immunoregulation; improved; in vivo; migration; mimicry; monocyte; mouse model; neovascularization; novel; novel strategies; particle; protein expression; receptor; recruit; regeneration function; regenerative; response; response to injury; wound healing

Project Summary At the heart of angiogenesis and biomaterial vascularization lies the inflammatory response, orchestrated primarily by macrophages, which dramatically shift phenotype over time in response to microenvironmental cues. In the normal response to injury, macrophages are initially pro-inflammatory (aka M1), and at later stages they are replaced by a mixed population referred to collectively as M2 that upregulate factors associated with resolution of the wound healing process. The extent of the diversity of this M2 population in particular is not known. At later stages of angiogenesis and biomaterial vascularization, M2 macrophages are generated 1) via transition from M1 macrophages, or 2) from direct differentiation of newly arriving monocytes. The differences between the M2 macrophages arising from each population have not been investigated. Preliminary data suggest that M1-derived M2 macrophages possess enhanced angiogenic functionality, and that biomaterials that transiently stimulate the initial M1 phase may enhance the subsequent response to M2-promoting biomaterials to achieve enhanced vascularization and healing. The overarching hypothesis of this project is that biomaterials that promote sequential M1 and M2 activation of the same population of macrophages will enhance vascularization. To test this hypothesis, this work has the following goals: 1) Determine the effects of M1 pre- polarization on the functional phenotype of M2 macrophages in crosstalk with blood vessels in vitro, using primary human macrophages, gene and protein expression profiling, and tissue-engineered models of angiogenesis. 2) Determine the effects of pro-inflammatory pre-treatment on the regenerative effects of IL4- releasing biomaterials in vivo, using biomaterials that temporally control the phenotype of host macrophages in a murine hindlimb ischemia model. 3) Determine the angiogenic effects in vivo of a biomaterial-mediated macrophage cell therapy strategy that intracellularly directs a single population of macrophages from M1 to M2. This latter strategy may result in particularly beneficial biomaterials for patients who suffer from impaired leukocyte trafficking, including patients with diabetes, autoimmune disease, or those undergoing chemotherapeutic treatment for cancer. This work will advance our understanding of how biomaterials can be designed to leverage both the inflammatory and regenerative functions of macrophages to enhance angiogenesis, which will allow us to develop new strategies to treat numerous diseases characterized by pathological angiogenesis, including heart and brain ischemia, atherosclerosis, and diabetes, among many others. In addition, this project proposes a novel approach to direct tissue revascularization by controlling the actions of both recruited and exogenously administered macrophages using biomaterials.

项目摘要 在血管生成和生物材料血管形成的核心是炎症反应， 主要是巨噬细胞，随着时间的推移，巨噬细胞会对微环境的提示做出反应，从而显著改变表型。 在对损伤的正常反应中，巨噬细胞最初是促炎细胞(又名M1)，在后来的阶段 被统称为M2的混合群体所取代，该群体上调与 解决伤口愈合过程。特别是M2人口的多样性程度并不是 为人所知。在血管生成和生物材料血管化的后期阶段，M2巨噬细胞是通过 来自M1巨噬细胞的过渡，或2)来自新到达的单核细胞的直接分化。其中的差异 在M2巨噬细胞之间产生的每个群体还没有被研究。初步数据 提示M1来源的M2巨噬细胞具有增强的血管生成功能，并且生物材料 短暂地刺激最初的M1阶段可能会增强随后对M2促进的反应 生物材料，以实现增强血管形成和愈合。这个项目的首要假设是 促进同一群巨噬细胞顺序激活M1和M2的生物材料将增强 血管形成。为了检验这一假说，这项工作有以下目标：1)确定M1预置的影响 M_2巨噬细胞与血管体外串扰中功能表型的极化 原代人巨噬细胞，基因和蛋白质表达谱，以及组织工程模型 血管生成。2)测定促炎预处理对IL-4再生效应的影响 体内释放生物材料，使用时间控制宿主巨噬细胞表型的生物材料 一种小鼠后肢缺血模型。3)测定生物材料在体内的血管生成效应。 巨噬细胞治疗策略，在细胞内引导单个巨噬细胞群从M1到M2。 后一种策略可能会为那些遭受损害的患者带来特别有益的生物材料 白细胞贩运，包括糖尿病、自身免疫性疾病或正在接受治疗的患者 癌症的化疗疗法。这项工作将促进我们对生物材料如何 旨在利用巨噬细胞的炎症和再生功能来增强 血管生成，这将使我们能够开发新的策略来治疗许多具有以下特征的疾病 病理性血管生成，包括心脏和脑缺血、动脉粥样硬化和糖尿病等 其他。此外，该项目提出了一种新的方法，通过控制组织血管重建来指导组织再血管化 利用生物材料招募和外源性给药巨噬细胞的行为。