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: 9340738
• 负责人: Kara Lorraine Spiller
• 金额: $ 5.49万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340738
• 关键词: Affect; Anastomosis - action; Atherosclerosis; Behavior; Biocompatible Materials; Biomimetics; Blood Vessels; Brain Ischemia; Cells; Coculture Techniques; Development; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Endothelial Cells; Exhibits; Functional disorder; Gene Expression; Genes; Goals; Growth; Growth Factor; Heart; Hypertension; In Vitro; Inflammatory; Inflammatory Response; Lead; Macrophage Activation; Mesenchymal Stem Cells; Molecular Profiling; Myocardial Ischemia; Osteoporosis; Pathologic; Pathologic Neovascularization; Peptide Signal Sequences; Pericytes; Phenotype; Process; Pulmonary Fibrosis; Recruitment Activity; Regulation; Signal Transduction; Testing; Therapeutic; Tissue Engineering; Tissues; Vascularization; Work; Wound Healing; angiogenesis; cytokine; design; experimental study; immunoregulation; improved; in vivo; injury and repair; macrophage; neovascularization; new growth; next generation sequencing; novel; novel strategies; public health relevance; response to injury; scaffold; three-dimensional modeling; tissue regeneration; tissue repair; transcriptome sequencing

 DESCRIPTION (provided by applicant): Diseases caused by insufficient or abnormal blood vessel growth affect a wide range of tissues, and include heart and brain ischemia, hypertension, atherosclerosis, pulmonary fibrosis, diabetes, and osteoporosis. At the heart of angiogenesis lies the inflammatory response, orchestrated primarily by macrophages. Changes in the behavior of macrophages have major effects on angiogenesis and vascularization of tissue engineering scaffolds that are designed to replace damaged tissues. The proposed work has two major goals: 1) to define the relationship between macrophages and angiogenesis, and 2) to develop a novel biomaterial platform to control macrophage behavior in order to encourage vascularization by the body's own cells. In normal wound healing, macrophages first exhibit a pro-inflammatory M1 phenotype, and then switch to an alternatively activated M2 phenotype. Although angiogenesis is a part of normal wound healing, the relative contributions of M1 and M2 macrophages to angiogenesis are not well understood. M2 macrophages can also be subdivided into two different phenotypes, M2a and M2c, each with distinct but poorly understood effects on angiogenesis. The overarching hypothesis of this work is that M1 and M2 (both M2a and M2c) macrophages function synergistically and sequentially to promote the growth of new blood vessels. Co-culture experiments between polarized macrophages and endothelial cells will be used to investigate how their crosstalk affects both the M1-to-M2 transition of macrophages and the phenotypic changes in endothelial cells that lead to sprouting and stabilization of new blood vessels. A 3D model of angiogenesis that tracks the behavior of endothelial cells and pericytes over 5 days will be used to probe the effects of changing the timing, duration, and sequence of signals secreted by the different macrophage phenotypes. Finally, macrophage regulation of angiogenesis will be evaluated in vivo using novel immunomodulatory drug delivery systems designed to recapitulate the normal sequence of M1 and M2 macrophage activation. This project will investigate the mechanisms of macrophage regulation of successful blood vessel growth, which will enhance our understanding of how it goes awry in pathological conditions. In addition, this project will result in a novel and biomimetc approach to direct scaffold vascularization by controlling the actions of host macrophages.

 描述（由适用提供）：由不足或异常的血管生长引起的疾病会影响广泛的组织，包括心脏和脑缺血，高血压，动脉粥样硬化，肺纤维化，糖尿病和骨质疏松症。血管生成的核心是炎症反应，由巨噬细胞精心策划。巨噬细胞行为的变化对旨在替代受损组织的组织工程支架的血管生成和血管化有重大影响。拟议的工作有两个主要目标：1）定义巨噬细胞与血管生成之间的关系，以及2）开发一种新型的生物材料平台来控制巨噬细胞行为，以鼓励人体自身细胞的血管化。在正常的伤口愈合中，巨噬细胞首先暴露了促炎的M1表型，然后切换到替代激活的M2表型。尽管血管生成是正常伤口愈合的一部分，但尚不清楚M1和M2巨噬细胞对血管生成的相对贡献。 M2巨噬细胞也可以细分为两种不同的表型，M2A和M2C，每个表型对血管生成的影响不同，但知之甚少。这项工作的总体假设是M1和M2（M2A和M2C）巨噬细胞协同和顺序地发挥作用，以促进新血管的生长。极化巨噬细胞和内皮细胞之间的共培养实验将用于研究它们的串扰如何影响巨噬细胞的M1-TO-M2转变以及内皮细胞的表型变化，从而导致新血管的发芽和稳定。在5天内跟踪内皮细胞和周细胞行为的3D血管生成模型将用于探测改变不同巨噬细胞表型分泌的时间，持续时间和信号序列的效果。最后，将使用新型免疫调节药物输送系统在体内评估血管生成的巨噬细胞调节，旨在概括M1和M2巨噬细胞激活的正常序列。该项目将研究成功血管生长的巨噬细胞调节的机制，这将增强我们对病理状况如何出现问题的理解。此外，该项目将通过控制宿主巨噬细胞的作用来导致一种新颖的生物IMIMETC方法来直接脚手架血管化。