The Mechanism of Immune-Vascular Crosstalk in Retinopathy

项目总结/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。的进步 新生儿护理，挽救了更小和更多的早产儿，他们处于ROP的高风险中。因此 ROP的发病率持续增加。消融手术破坏视网膜和抗血管内皮生长 血管内皮生长因子（VEGF）治疗可能会导致脆弱新生儿血管生长的全身抑制。长期 目的是了解ROP发展的分子机制，以设计早期预防性治疗。 炎症和免疫功能的变化显然与ROP有关，但标准的抗炎药物 例如类固醇或NSAIDS对ROP无效，并且控制炎症的方法尚不清楚。然而，在这方面， 免疫细胞是细胞因子和生长因子的来源，其可与内皮细胞相互作用并有助于 血管壁结构和功能异常的发展。越来越多的证据表明， 骨髓细胞在视网膜血管发育、重塑、修复和吻合中的关键作用。髓样细胞如 如小胶质细胞，在炎症损伤后迅速活化并调节血管生成。总体目标 本申请旨在鉴定视网膜病中免疫-血管相互作用的机制。了解 视网膜病变中的病理性免疫变化目前受到关于 健康眼睛中常驻免疫细胞的生理学和功能。细胞因子信号转导抑制因子3（SOCS 3）是 一种控制先天性和适应性免疫、组织炎症、细胞因子产生的关键调节因子， 巨噬细胞极化，我们报道SOCS 3可以抑制病理性眼血管生成，因此， SOCS 3是介导眼部新生血管中免疫-血管相互作用的重要免疫调节因子 阵我们发现，骨髓源性免疫细胞中SOCS 3的缺失显著增加了病理性视网膜病变， 氧诱导视网膜病变模型ROP中的新血管形成。我们假设骨髓SOCS 3调节 通过调节视网膜炎症、免疫细胞活化和募集， 控制视网膜病变。这项研究的基本原理是，了解 ROP的发展有可能发展ROP的治疗，现在每年影响约16，000名美国婴儿。 我们将用三个目标来检验这个假设。目的1：确定髓样SOCS 3是否控制病理性视网膜病变; 目的2：确定髓样SOCS 3是否通过调节SOCS 3的募集和激活来控制视网膜病变。 目的3：确定髓样SOCS 3是否通过免疫细胞进入视网膜来控制免疫-血管串扰; 调节视网膜炎性蛋白。这项研究是创新的，因为它代表了一个 通过确定免疫血管串扰的分子机制， 来控制病理性视网膜病变这项研究具有重要意义，因为它将提供一种新的靶点 （SOCS 3/免疫血管串扰）用于开发具有广泛翻译的治疗策略， 在预防和治疗ROP和广泛的其他血管性眼病中具有重要意义。

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.