The Mechanism of Immune-Vascular Crosstalk in Retinopathy

项目摘要/摘要 早产儿视网膜病变(ROP)是导致儿童失明和残疾的主要原因。随着技术的进步 新生儿护理，较小和更多的早产儿被挽救，他们是ROP的高危人群。因此， ROP的发生率继续增加。消融手术破坏视网膜并抑制血管内皮生长 血管内皮生长因子(VEGF)治疗可能导致脆弱新生儿血管生长的全身性抑制。长期的 目的是了解ROP发生的分子机制，以设计出更早的预防性治疗。 炎症和免疫功能的改变显然与ROP有关，但标准的抗炎药物 如类固醇或非类固醇类药物对ROP无效，控制炎症的方法尚不清楚。然而， 免疫细胞是细胞因子和生长因子的来源，这些细胞因子和生长因子可能与内皮细胞相互作用，并对 导致血管壁结构和功能异常的发展。越来越多的证据表明 髓系细胞在视网膜血管发育、重塑、修复和吻合中的关键作用。髓系细胞 作为小胶质细胞，在炎性损伤后迅速激活，并调节血管生成。年的总体目标 这一应用是为了确定视网膜病变中免疫-血管相互作用的机制。了解 视网膜病变的病理性免疫变化目前受到相对缺乏的信息的限制 健康眼内常驻免疫细胞的生理和功能。细胞因子信号转导抑制因子3(SOCS3)是 一种控制先天免疫和获得性免疫、组织炎症、细胞因子产生和 巨噬细胞极化，我们报道了SOCS3可以抑制病理性眼血管生成，因此， SOCS3是一种重要的免疫调节剂，在眼球新生血管形成中介导免疫-血管相互作用 队形。我们发现髓系来源的免疫细胞中SOCS3的丢失显著增加了病理性视网膜 氧诱导视网膜病变模型ROP中的新生血管。我们假设髓系SOCS3调节 免疫血管串扰通过调节视网膜炎症、免疫细胞激活和募集 控制视网膜病变。这项拟议研究的基本原理是，理解人类免疫缺陷的分子机制 ROP的发展具有开发ROP治疗的潜力，目前ROP每年影响美国约16,000名婴儿。 我们将通过三个目标来检验这一假设。目的1：确定髓系SOCS3是否控制病理性视网膜病变； 目的2：确定髓系SOCS3是否通过调节视网膜细胞的募集和激活来控制视网膜病变 免疫细胞进入视网膜；目标3：确定髓系SOCS3是否通过 视网膜炎症蛋白的调节。这项拟议的研究具有创新性，因为它代表了 通过确定免疫-血管串扰的分子机制，从根本上改变现状 控制病理性视网膜病变。这项拟议的研究意义重大，因为它将提供一个新的目标 (SOCS3/免疫血管串扰)，用于开发具有广泛翻译能力的治疗策略 在预防和治疗ROP和其他一系列血管性眼病方面具有重要意义。

PROJECT SUMMARY/ABSTRACT Retinopathy of prematurity (ROP) is a major cause of blindness and disability in children. With advances in neonatal care, smaller and more premature infants are saved who are at high risk for ROP. Therefore, the incidence of ROP continues to increase. Ablation surgery destroys retina and anti-Vascular endothelial growth factor (VEGF) treatment may cause systemic suppression of vessel growth in fragile neonates. The long-term goal is to understand the molecular mechanisms of ROP development to devise earlier preventative therapies. Inflammation and changes in immune function are clearly involved in ROP, but standard anti-inflammatory drugs such as steroids or NSAIDS are not effective in ROP and the way to control inflammation is not clear. However, immune cells are a source of cytokines and growth factors that may interact with the endothelial cells and contribute to the development of structural and functional abnormalities of the vessel wall. There is increasing evidence for the critical role of myeloid cells in retinal vascular development, remodeling, repair, and anastomosis. Myeloid cells such as microglia, are rapidly activated after an inflammatory insult and modulate angiogenesis. The overall objective in this application is to identify the mechanism of immune-vascular interaction in retinopathy. Understanding of pathological immune changes in the retinopathy is currently limited by a relative paucity of information about the physiology and function of resident immune cells in the healthy eye. Suppressor of cytokine signaling 3 (SOCS3) is a critical regulator that controls innate and adaptive immunity, tissue inflammation, cytokine production, and macrophage polarization, we reported that SOCS3 can suppress pathological ocular angiogenesis, therefore, SOCS3 is an essential immune-regulator that mediates immune-vascular interaction in ocular neovascularization formation. We found loss of SOCS3 in immune cells of myeloid origin significantly increased pathological retinal neovascularization in oxygen-induced retinopathy modeling ROP. We hypothesize that myeloid SOCS3 regulates immune-vascular crosstalk through modulating retinal inflammation, immune cell activation and recruitment to control retinopathy. The rationale for the proposed research is that understanding the molecular mechanisms of ROP development has the potential to develop treatment of ROP that now affects ~16,000 US infants per year. We will test this hypothesis with three Aims. Aim 1: To determine if myeloid SOCS3 controls pathological retinopathy; Aim 2: To determine if myeloid SOCS3 controls retinopathy through modulating the recruitment and activation of immune cells into the retina; Aim 3: To determine if myeloid SOCS3 controls immune-vascular crosstalk through modulation of retinal inflammatory proteins. The proposed research is innovative because it represents a substantive departure from the status quo by identifying the molecular mechanisms of immune-vascular crosstalk to control pathological retinopathy. The proposed research is significant because it will provide a novel target (SOCS3/immune-vascular crosstalk) for developing therapeutic strategies that have broad translational importance in the prevention and treatment of ROP and a wide range of other vascular eye diseases.