Inflammation and retinopathy of prematurity

项目摘要 早产儿视网膜病变（ROP）是影响早产儿或低出生率儿童的最常见的疾病之一。 出生体重的婴儿，是长期的视觉和非视觉相关的发病率的主要原因。ROP是一个 低出生体重幸存者的疾病，但在两种疾病中， 产前和产后时期。限制暴露于过量的氧气和最近出现的抗- 血管生成化合物是ROP治疗的基础，但这些方法由以下因素复合而成： 低出生体重儿的死亡率增加和认知结果较差， 较低的补充氧气或接受贝伐单抗（抗VEGF）治疗ROP。这些发现表明， 对疾病发病机制以及共病和炎症对疾病的影响认识不足， ROP开发。视网膜新生血管形成风险人群的临床观察， 在1型神经纤维瘤病（NF 1）中观察到的炎症提示炎性单核细胞和 巨噬细胞在异常视网膜血管生成和ROP中起重要作用。神经纤维蛋白， 由引起NF 1的基因编码，作为巨噬细胞极化的主要调节剂起作用， Nf 1基因的失活突变导致促炎单核细胞的动员， 巨噬细胞的研究。缺乏神经纤维蛋白的巨噬细胞呈现一种独特的分子 和代谢表型，其特征在于活性氧和氮的产生增加 物种和过度依赖糖酵解通过上调磷酸果糖激酶-1（PFK-1）的活性。 此外，缺乏神经纤维蛋白的巨噬细胞是促血管生成的，但也支持病理性视网膜病变。 新生血管形成在目标1中，我们将询问神经纤维蛋白调节的通路， 炎症巨噬细胞极化，以确定它们如何促进内皮细胞增殖， 迁移和毛细管形成。目的2将检查神经纤维蛋白酶对葡萄糖的摄取和利用。 使用特别关注巨噬细胞的体外和体内技术的缺陷巨噬细胞 因此，本发明涉及作为治疗/预防视网膜新生血管形成的治疗靶点的代谢。最后在 目的3，我们将利用试验数据证明炎症单核细胞亚群的动员， 严重ROP的新生儿。在这里，我们将纵向检查循环炎性单核细胞， 新生儿“有严重ROP的风险”，以鉴定离散的单核细胞亚群作为ROP的生物标志物， 确定神经纤维蛋白调节的信号传导对炎症单核细胞动员的作用， 新生儿ROP。在他们的结论中，拟议的研究将确定炎症的贡献。 巨噬细胞对病理性视网膜新生血管形成的影响，并鉴定需要 治疗

PROJECT SUMMARY Retinopathy of prematurity (ROP) is among the most common morbidities affecting premature or low birth weight infants and is a major cause of long-term visual and non-vision related morbidity. ROP is a disease of low birth weight survivors, but is often preceded temporally by inflammatory conditions in both the prenatal and postnatal period. Limiting exposure to excess oxygen and the recent advent of anti- angiogenic compounds are the foundation of ROP treatment, but these approaches are compounded by increased mortality and poorer cognitive outcomes in low birth weight infants who are maintained at lower supplemental oxygen or received bevacizumab (anti-VEGF) for ROP. These findings indicate a poor understanding of disease pathogenesis and contribution of co-morbid diseases and inflammation to ROP development. Clinical observations of persons at risk for retinal neovascularization and inflammation, as seen in neurofibromatosis type 1 (NF1), suggest that inflammatory monocytes and macrophages play a vital role in aberrant retinal angiogenesis and ROP. Neurofibromin, the protein encoded by the gene causing NF1, functions as a master regulator of macrophage polarization, and inactivating mutations in the Nf1 gene result in mobilization of pro-inflammatory monocytes and macrophages in mice and humans. Neurofibromin-deficient macrophages take on a distinct molecular and metabolic phenotype, characterized by enhanced production of reactive oxygen and nitrogen species and over-dependence on glycolysis via upregulation of phosphofructokinase-1 (PFK-1) activity. Further, neurofibromin-deficient macrophages are pro-angiogenic, but also support pathologic retinal neovascularization. In Aim 1, we will interrogate neurofibromin-regulated pathways that induce inflammatory macrophage polarization to identify how they promote endothelial cell proliferation, migration, and capillary formation. Aim 2 will examine glucose uptake and utilization in neurofibromin- deficient macrophages using in vitro and in vivo techniques with specific focus on macrophage metabolism as a therapeutic target for the treatment/prevention of retinal neovascularization. Finally, in Aim 3, we will capitalize on pilot data demonstrating a mobilization of inflammatory monocyte subsets in neonates with severe ROP. Here, we will longitudinally examine circulating inflammatory monocytes in neonates “at risk” for severe ROP to identify discrete monocyte subsets as a biomarker for ROP and define the contribution of neurofibromin-regulated signaling to inflammatory monocyte mobilization in neonates with ROP. At their conclusion, the proposed studies will define the contribution of inflammatory macrophages to pathologic retinal neovascularization and identify a biomarker for severe ROP requiring treatment.