Inflammation and retinopathy of prematurity

早产儿炎症和视网膜病变

• 批准号: 9918406
• 负责人: Brian Kevin Stansfield
• 金额: $ 43.72万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918406
• 关键词: 6-Phosphofructo-2-kinase; 6-Phosphofructokinase; Acute; Affect; Biological Markers; Biological Models; Blood Vessels; Blood capillaries; CCL2 gene; CD14 gene; Cell Proliferation; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Cognitive; Coupled; Data; Dependence; Development; Disease; Endothelial Cells; Enzymes; Exhibits; Exposure to; FCGR3B gene; Flow Cytometry; Foundations; Frequencies; Fructose; Genes; Glycolysis; Goals; Human; Hyperoxia; In Vitro; Individual; Infant; Inflammation; Inflammation Mediators; Inflammatory; Low Birth Weight Infant; Mediating; Metabolism; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; NF1 gene; Neurofibromatosis 1; Nitrogen; Outcome; Oxygen; Paper; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathway interactions; Persons; Phase; Phenotype; Play; Population; Predisposition; Prevention; Process; Production; Property; Protein Isoforms; Proteins; Publishing; RNA Interference; Resolution; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Risk; Role; Signal Transduction; Survivors; TNF gene; Techniques; Testing; Therapeutic; Up-Regulation; Very Low Birth Weight Infant; Visual; base; bevacizumab; clinically relevant; comorbidity; cytokine; defined contribution; early detection biomarkers; experience; glucose metabolism; glucose uptake; in vivo; inhibitor/antagonist; macrophage; metabolic phenotype; migration; molecular phenotype; monocyte; mortality; neonate; neovascular; new therapeutic target; novel; postnatal period; premature; prenatal; response; retinal angiogenesis; therapeutic target

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.

项目摘要 早产视网膜病变（ROP）是影响过早或低的最常见病因之一 出生体重婴儿，是长期视觉和非视觉相关发病率的主要原因。 ROP是一个 低出生体重存活的疾病，但通常在两者中暂时出现炎症状况 产前和产后期。限制暴露于多余的氧气以及最近的抗氧气冒险 血管生成化合物是ROP治疗的基础，但是这些方法是由 维持在 较低的补充氧或接收的bevacizumab（抗VEGF）用于ROP。这些发现表明 对疾病发病机理的不良理解以及合并症的贡献以及炎症对 ROP开发。临床观察到有永久性新血管形成风险的人 如1型神经纤维瘤病（NF1）所见，炎症表明炎症单核细胞和 巨噬细胞在异常残留血管生成和ROP中起着至关重要的作用。神经纤维蛋白，蛋白质 由引起NF1的基因编码，作为巨噬细胞极化的主要调节剂，并且 NF1基因中的灭活突变导致动员促炎单核细胞和 小鼠和人类的巨噬细胞。神经纤维蛋白缺乏巨噬细胞采用独特的分子 和代谢表型，其特征是活性氧和氮的产生增强 通过上调磷酸果酶-1（PFK-1）活性，物种和对糖酵解的过度依赖性。 此外，神经纤维蛋白缺陷巨噬细胞具有亲血管生成，但也支持病理性视网膜 新血管形成。在AIM 1中，我们将询问影响神经纤维蛋白调节的途径 炎症性巨噬细胞极化以确定它们如何促进内皮细胞增殖， 迁移和毛细血管形成。 AIM 2将检查神经纤维蛋白的葡萄糖摄取和利用 使用体外和体内技术缺乏巨噬细胞，具体专注于巨噬细胞 代谢作为治疗/预防残留新血管的治疗靶点。最后，在 AIM 3，我们将利用试验数据，证明动员炎症单核细胞集中 新生儿患有严重的ROP。在这里，我们将纵向检查循环的炎症单核细胞 新生儿“处于风险”中，严重的ROP识别离散的单核细胞子集作为ROP和ROP的生物标志物 定义神经纤维蛋白调节的信号传导对炎症单核细胞动员的贡献 新生儿与ROP。在他们的结论中，拟议的研究将定义炎症的贡献 巨噬细胞到病理视网膜新血管形成，并确定一个生物标志物，以进行严重的ROP 治疗。