The role of phagocytosis for modulation and clearance of pathological angiogenesis.

吞噬作用在调节和清除病理性血管生成中的作用。

• 批准号: 432300237
• 负责人: Dr. Anne Klotzsche-von Ameln
• 金额: --
• 依托单位: Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432300237?language=en
• 关键词: role; phagocytosis; modulation; clearance; pathological

Proliferative retinopathies, such as retinopathy of prematurity (ROP) or proliferative diabetic retinopathy (DR) represent an important health burden being a major cause of blindness. Proliferative retinopathies are characterized by pathological neovascularization (angiogenesis) in the retina leading to the formation of aberrant neo-vessels, so called tufts, which protrude beyond the retinal inner limiting membrane into the vitreous cavity, causing severe vision impairment. Interestingly we observed, that endothelial cell apoptosis is a hallmark of these tufts, which might initiate the process of tuft regression and vessel normalization, observed in ROP. A major component of the pathophysiology underlying retinopathy is the close interplay of endothelial cells with inflammatory cells that is regulated by specific components of the micro-environment, e.g. local hypoxia/ reoxygenation. The aim of the present proposal is to investigate whether the phagocytic property of microglia is involved in the clearance of apoptotic endothelial cells in the pathological tufts during ROP and thus modulates pathological angiogenesis in the context of proliferative retinopathy. We will address this question by engaging microglia-specific deletion of SOCS3 as a specific tool, as we have preliminary evidence, that this factor regulates phagocytosis. In particular, we will assess (I) whether microglial Socs3, with its altered phagocytic capacity, can affect in-vivo physiological and pathological retinal angiogenesis by engaging the mouse hypoxia-induced vasoproliferative retinopathy of prematurity (ROP) model. (II) In addition, we want to identify with the help of reporter mice, whether in vivo endothelial cells or endothelial cell particles are taken up by microglia and we will study the expression kinetics of pro- and anti-phagocytic molecules in the mouse ROP-model. (III) Moreover we will analyse whether hypoxia/reoxigenation and/ or the uptake of apoptotic endothelial cells are stimuli to reprogram myeloid cells towards a pro-efferocytic and pro-resolving phenotype. (IV) Finally, as a proof of principle, we will evaluate if the modulation of apoptotic cell clearance (efferocytosis) by mononuclear cells can be used as a new therapeutic strategy for the treatment of pathological vascular disorders. Despite the progress made in the last years, understanding the pathogenesis of retinopathy, the knowledge of the underlying mechanisms and the interaction of endothelial and inflammatory cells is still insufficient and therapeutics are limited. Therefore, this proposal is highly innovative, since it will provide novel mechanistic insights into the role of microglia cell phagocytic activity in the context of proliferative retinopathy. The improved understanding of the underlying mechanism may subsequently lead to novel therapeutic concepts to prevent blindness.

增殖性视网膜病变，如早产儿视网膜病变（ROP）或增殖性糖尿病视网膜病变（DR）是一种重要的健康负担，是失明的主要原因。增殖性视网膜病变的特征是视网膜的病理性新生血管（血管生成）导致异常新生血管的形成，即所谓的簇状血管，这些血管突出视网膜内限制膜进入玻璃体腔，造成严重的视力损害。有趣的是，我们观察到内皮细胞凋亡是这些簇状细胞的一个标志，它可能启动簇状细胞回归和血管正常化的过程，在ROP中观察到。视网膜病变病理生理学的一个主要组成部分是内皮细胞与炎症细胞的密切相互作用，这种相互作用是由微环境的特定组成部分调节的，例如局部缺氧/再氧化。本研究的目的是研究小胶质细胞的吞噬特性是否参与ROP期间病理丛中凋亡内皮细胞的清除，从而调节增殖性视网膜病变背景下的病理性血管生成。我们将通过将SOCS3的小胶质细胞特异性缺失作为一种特定工具来解决这个问题，因为我们有初步证据表明，该因子调节吞噬作用。特别是，我们将通过小鼠缺氧诱导的血管增殖性早产儿视网膜病变（ROP）模型来评估(I)吞噬能力改变的小胶质细胞Socs3是否会影响体内生理性和病理性视网膜血管生成。（II）此外，我们想借助报告小鼠鉴定体内内皮细胞或内皮细胞颗粒是否被小胶质细胞吞噬，我们将研究促吞噬分子和抗吞噬分子在小鼠rop模型中的表达动力学。（III）此外，我们将分析缺氧/再氧化和/或凋亡内皮细胞的摄取是否刺激髓细胞重编程，使其向促红细胞增生和促溶解表型转变。（IV）最后，作为原理证明，我们将评估单核细胞对凋亡细胞清除（efferocytosis）的调节是否可以作为一种新的治疗策略用于治疗病理性血管疾病。尽管在过去几年中取得了进展，但对视网膜病变的发病机制、潜在机制以及内皮细胞和炎症细胞的相互作用的了解仍然不足，治疗方法也有限。因此，这一建议是高度创新的，因为它将为小胶质细胞吞噬活性在增殖性视网膜病变中的作用提供新的机制见解。对潜在机制的理解的提高可能随后导致新的治疗概念，以防止失明。