Retinopathy of prematurity (ROP) occurs in 50 to 80% of preterm babies born weighing less than 1250 grams. The NYPD-PRC (New York Pediatric Developmental Pharmacology Research Consortium) was formed as a unique multidisciplinary research team of neonatal pharmacologist, retina investigators, neonatologists and pharmaceutical scientists to define the molecular events leading to ROP and to develop effective and safe pharmacologic strategies to prevent it. The overarching hypothesis is that repeated hyperoxic/hypoxic episodes promoting aberrant ocular VEGF signaling, dysregulated angiogenesis and vasoproliferation can be modulated or prevented by synergistic interventions of caffeine and systemic ibuprofen or ocular NSAID local drops. Using novel intervention strategies and unique approaches, three distinct but highly inter-related study proposals will test various hypotheses and specific aims in newborn rats, retinal endothelial tip cell cultures and in preterm newborn infants born <28 weeks or weighing <1250 grams. Protocol 1 will determine the efficacy and safety of ocular ibuprofen or ketorolac with systemic caffeine as well as the critical timing of intervention for the prevention of oxygen induced retinopathy in newborn rat model of OIR. Protocol II will examine the behavior of retinal endothelial tip cells and their dynamic relationship with astrocytes in the setting of oxidative stress (hyperoxia/hypoxia cycling);and to determine whether ibuprofen co-administered with caffeine will preserve tip cell quiescence. Once studies on additional safety, efficacy and critical timing of intervention (vasoobliterative or vaso-proliferative phase) are completed, Protocol III will be implemented in preterm newborns weighing <1250 grams, to test the safety, efficacy, pharmacodynamics and pharmacogenomics of systemic caffeine with or without IV ibuprofen or with or without local NSAID eye drops (ketorolac) in a multicenter, randomized, open label study to prevent ROP (all stages). Unique pharmacometric analyses of all 3 protocols provide novel data on ocular drug transport and action during development. The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness.

Public Health Relevance

Retinopathy of Prematurity or ROP occurs in 2 out of 3 small babies born prematurely and treated with oxygen. ROP is the most common cause of blindness in children. Understanding the molecular events leading to ROP and providing novel, effective and safe drug interventions will avert a lifetime of blindness, disability and darkness.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD071594-03
Application #
8473232
Study Section
Special Emphasis Panel (ZHD1-DSR-A (50))
Program Officer
Zajicek, Anne
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$709,379
Indirect Cost
$222,339
Name
Suny Downstate Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Beharry, Kay D; Cai, Charles L; Ahmad, Taimur et al. (2018) Impact of Chronic Neonatal Intermittent Hypoxia on Severity of Retinal Damage in a Rat Model of Oxygen-Induced Retinopathy. J Nat Sci 4:
Nicolau, Yona; Bany-Mohammed, Fayez; Cai, Charles L et al. (2018) SiRNA silencing of VEGF, IGFs, and their receptors in human retinal microvascular endothelial cells. Am J Transl Res 10:1990-2003
Cai, Charles; Ahmad, Taimur; Valencia, Gloria B et al. (2018) Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver. Growth Horm IGF Res 41:54-63
Valencia, Arwin M; Abrantes, Maria A; Hasan, Jamal et al. (2018) Reactive Oxygen Species, Biomarkers of Microvascular Maturation and Alveolarization, and Antioxidants in Oxidative Lung Injury. React Oxyg Species (Apex) 6:373-388
Beharry, Kay D; Cai, Charles L; Valencia, Gloria B et al. (2018) Human retinal endothelial cells and astrocytes cultured on 3-D scaffolds for ocular drug discovery and development. Prostaglandins Other Lipid Mediat 134:93-107
Wang, Xue; Niu, Jin; Li, Jun et al. (2018) Temporal Effects of Combined Birinapant and Paclitaxel on Pancreatic Cancer Cells Investigated via Large-Scale, Ion-Current-Based Quantitative Proteomics (IonStar). Mol Cell Proteomics 17:655-671
Quan, Michelle; Cai, Charles L; Valencia, Gloria B et al. (2017) MnTBAP or Catalase Is More Protective against Oxidative Stress in Human Retinal Endothelial Cells Exposed to Intermittent Hypoxia than Their Co-Administration (EUK-134). React Oxyg Species (Apex) 3:47-65
Shen, Xiaomeng; Shen, Shichen; Li, Jun et al. (2017) An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts. J Proteome Res 16:2445-2456
Valencia, Arwin M; Cai, Charles L; Tan, Jeffrey et al. (2017) Intravitreal bevacizumab alters type IV collagenases and exacerbates arrested alveologenesis in the neonatal rat lungs. Exp Lung Res 43:120-133

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