Proangiogenic M2-type macrophages and choroidal neovascularization

促血管生成 M2 型巨噬细胞和脉络膜新生血管

• 批准号: 10681491
• 负责人: Alexander Georg Marneros
• 金额: $ 42.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681491
• 关键词: ABL1 gene; Ablation; Address; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antigen-Antibody Complex; Aqueous Humor; Area; Attenuated; Biological Assay; Blood Vessels; Cells; Chemicals; Choroidal Neovascularization; Data; Data Analyses; Disease; Drug Screening; Endothelium; Event; Exudative age-related macular degeneration; Eye; Genetic; Glucocorticoids; Heat-Shock Proteins 90; Histone Deacetylase; Histone Deacetylase Inhibitor; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Injections; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-6; Lasers; Lesion; MAP2K1 gene; MEKs; Macrophage; Mediating; Membrane; Modeling; Molecular; Molecular Target; Mus; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Population; Process; Proteomics; Resources; Role; Signal Transduction; Site; Testing; Therapeutic; Time; VEGFA gene; angiogenesis; cellular targeting; clinically relevant; cytokine; experimental study; genetic approach; in vivo; inhibitor; innovation; macrophage-derived chemokine; mouse model; neovascularization; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; phosphoproteomics; prevent; small molecule; therapeutic target

SUMMARY Macrophages infiltrate the site of inflammation and polarize to either antiangiogenic M1-type macrophages or proangiogenic M2-type macrophages, depending on the presence of various cytokines and other external factors. Proangiogenic M2-type macrophages are major contributors to inflammatory angiogenesis in many common diseases, in part by secreting proangiogenic factors, such as VEGF-A or IL-1b. Notably, M2-type macrophages accumulate in areas of choroidal neovascularization (CNV) in patients with neovascular AMD. The increase in M2-type macrophage-derived cytokines in eyes of patients with neovascular AMD has implicated this cell population as a major driver of CNV pathogenesis. This hypothesis is further supported by the observation of an accumulation of M2-type macrophages in laser-induced CNV or in a genetic VEGF-A-induced mouse model of neovascular AMD. Ablation of macrophages in laser-induced CNV, which are predominantly M2-type macrophages, blocked CNV, whereas administration of M2-type macrophages in the eye promoted CNV. Based on these findings we propose that pharmacologic therapies that prevent M2-type polarization of macrophages can serve as a novel approach to potently inhibit CNV progression in patients with neovascular AMD. The limited understanding of the signaling mechanisms that are regulating M1- versus M2-type polarization of macrophages has hindered the identification of molecular targets and pharmacologic inhibitors to selectively block M2-type macrophage polarization. To address this unmet need, we have performed global quantitative time-course proteomics and phosphoproteomics and identified kinase activation events that are associated with M1- versus M2-type macrophage polarization. Furthermore, we identified in chemical screens pharmacologic inhibitors of M2-type polarization that selectively block M2- but not M1-type polarization. Thus, the combination of these two approaches provides us now with a unique resource to establish novel therapies that selectively block proangiogenic M2- but not antiangiogenic M1-type macrophages in CNV. In proof-of-principle experiments we can show that two of the identified inhibitors, the MEK inhibitor trametinib and the HDAC inhibitor panobinostat, blocked M2-type macrophage polarization in CNV lesions and potently inhibited CNV lesion formation in laser- induced CNV experiments. Our proposed experiments will test identified kinase and non-kinase inhibitors in a systematic manner for their ability to selectively block M2-type polarization in detailed in vitro experiments as well as in three well-established mouse models of neovascular AMD. Our proposal is based on extensive preliminary data that provide a strong scientific premise. The proposed experiments have high rigor and important clinical relevance and will likely lead to novel therapeutic approaches for neovascular AMD.

概括 巨噬细胞渗入炎症部位，并极化抗血管生成的M1型巨噬细胞或 促血管生成M2型巨噬细胞，具体取决于各种细胞因子和其他外部的存在 因素。促血管生成的M2型巨噬细胞是许多导致炎症性血管生成的主要因素 常见疾病，部分是通过分泌促血管生成因素（例如VEGF-A或IL-1B）。值得注意的是，M2型 巨噬细胞在新生血管AMD患者的脉络膜新血管形成（CNV）地区积累。这 新生血管AMD患者眼中M2型巨噬细胞衍生的细胞因子的增加已暗示这一点 细胞种群是CNV发病机理的主要驱动力。观察进一步支持了这一假设 M2型巨噬细胞在激光诱导的CNV或遗传VEGF-A诱导的小鼠中的积累 新生血管AMD的模型。激光诱导的CNV中巨噬细胞的消融，主要是M2型 巨噬细胞，阻塞CNV，而在眼睛中施用M2型巨噬细胞促进了CNV。基于 在这些发现中，我们建议预防M2型巨噬细胞极化的药理学疗法 可以作为一种新型方法，可在新血管AMD患者中有效抑制CNV进展。有限公司 了解调节M1与M2型巨噬细胞极化的信号传导机制 阻碍了分子靶标和药理抑制剂的鉴定，以选择性阻断M2型 巨噬细胞极化。为了满足这种未满足的需求，我们执行了全球定量时间课程 蛋白质组学和磷酸蛋白质组学，并鉴定出与M1-与M1相关的激酶激活事件 M2型巨噬细胞极化。此外，我们在化学筛选中确定了 M2型极化，有选择地阻断M2-而不是M1型极化。因此，这两个的结合 方法现在为我们提供了一种独特的资源来建立新型疗法，以有选择地阻止 CNV中的促血管生成M2-但不是抗血管生成的M1型巨噬细胞。在原则实验中，我们 可以证明MEK抑制剂Trametinib和HDAC抑制剂Panobinostat，两个已鉴定的抑制剂， 在CNV病变中阻塞的M2型巨噬细胞极化，并有效抑制了激光 - 诱导CNV实验。我们提出的实验将测试A中鉴定的激酶和非激酶抑制剂 有系统的方式，可以在详细的体外实验中选择性地阻断M2型极化为能力 以及在三种良好的新生血管AMD的小鼠模型中。我们的建议基于广泛 提供强大科学前提的初步数据。提出的实验具有很高的严格性，并且 重要的临床相关性，可能会导致新型的新血管AMD治疗方法。