Understanding and Controlling Macrophage Behavior in Angiogenesis

 描述（由申请人提供）：由血管生长不足或异常引起的疾病影响广泛的组织，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，主要由巨噬细胞协调。巨噬细胞行为的改变对用于替代受损组织的组织工程支架的血管生成和血管化具有重要影响。这项工作有两个主要目标：1）确定巨噬细胞和血管生成之间的关系，2）开发一种新的生物材料平台来控制巨噬细胞的行为，以促进人体自身细胞的血管形成。在正常的伤口愈合中，巨噬细胞首先表现出促炎性M1表型，然后转变为替代活化的M2表型。虽然血管生成是正常伤口愈合的一部分，但M1和M2巨噬细胞对血管生成的相对贡献还不清楚。M2巨噬细胞还可以细分为两种不同的表型，M2a和M2c，每种表型对血管生成具有不同但知之甚少的作用。这项工作的首要假设是，M1和M2（M2a和M2c）巨噬细胞协同作用，依次促进新血管的生长。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至M2转变和内皮细胞中导致新血管发芽和稳定的表型变化。血管生成的3D模型跟踪内皮细胞和周细胞在5天内的行为，将用于探测改变不同巨噬细胞表型分泌的信号的时间、持续时间和序列的影响。最后，巨噬细胞调节血管生成将在体内评价使用新的免疫调节药物递送系统，旨在概括M1和M2巨噬细胞活化的正常序列。这个项目将研究巨噬细胞调节成功血管生长的机制，这将提高我们对它在病理条件下如何出错的理解。此外，该项目还将通过控制宿主巨噬细胞的作用来指导支架血管化。

 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.