Inflammation and retinopathy of prematurity

项目总结 早产儿视网膜病变(Rop)是影响早产儿或早产儿的最常见的疾病之一。 出生体重和出生体重是导致长期视力和非视力相关疾病的主要原因。ROP是一种 低出生体重幸存者的疾病，但通常先于两者的炎症情况 产前和产后时期。限制暴露在过量氧气中和最近出现的反- 血管生成化合物是ROP治疗的基础，但这些方法与 低出生体重儿的死亡率增加和认知结果较差 降低补充氧气或接受贝伐单抗(抗血管内皮生长因子)治疗ROP。这些发现表明 对疾病的发病机制和共病与炎症的贡献认识不足 ROP开发。视网膜新生血管和视网膜新生血管高危人群的临床观察 炎症，如在1型神经纤维瘤病(NF1)中所见，表明炎性单核细胞和 巨噬细胞在异常的视网膜血管生成和ROP中起重要作用。神经纤维蛋白，一种蛋白质 由引起NF1的基因编码，起着巨噬细胞极化的主要调节作用，并且 NF1基因失活突变导致促炎性单核细胞动员和 小鼠和人类的巨噬细胞。神经纤维蛋白缺陷型巨噬细胞呈现出独特的分子特征 代谢表型，特征是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，神经纤维蛋白缺乏的巨噬细胞是促血管生成的，但也支持病理性视网膜。 新生血管。在目标1中，我们将询问神经纤维蛋白调节的通路，这些通路导致 炎性巨噬细胞极化以确定它们如何促进内皮细胞增殖， 运移和毛细管形成。AIM 2将研究神经纤维蛋白对葡萄糖的摄取和利用。 以巨噬细胞为研究重点的体内和体外缺陷巨噬细胞技术 代谢作为治疗/预防视网膜新生血管的靶点。最后，在 目的3，我们将利用试点数据显示炎性单核细胞亚群在 重度ROP的新生儿。在这里，我们将纵向检查循环炎性单核细胞在 新生儿有严重ROP的风险以确定离散单核细胞亚群作为ROP的生物标志物 明确神经纤维素调节的信号在炎性单核细胞动员中的作用 患有ROP的新生儿。在他们的结论中，拟议的研究将定义炎症的贡献 巨噬细胞与病理性视网膜新生血管的关系及寻找严重ROP的生物标志物 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.