The pharmacometrics core will provide modeling and simulation platforms for the construction of genomic and proteomic-based disease progression models to understand the in vivo dynamics of oxygen-induced retinopathy (OIR) and the complex interrelationships with combination nonsteroidal anti-inflammatory drug (NSAID) and systemic caffeine regimens. Our population-based approach allows for the systematic evaluation of patient, molecular, and environmental specific characteristics that explain inter-subject variability in the time-course of disease. Quantitative relationships will be developed to capture the temporal aspects of biomarker expression that will be used to test competing hypotheses of the extent to which treatment and co-factors modify disease progression. Such information may also be used to optimize the selection of dose and administration schedules of such combination drug regimens. Our core faculty members have extensive experience in the development of drug exposure-response relationships. Modeling and the determination of drug and system specific properties may be extended to enhance clinical trial design and data analysis, improve screening of compounds in development, and identify prognostic risk factors. For Protocol 1, nonlinear mixed effects pharmacokinetic/pharmacodynamic (PK/PD) models will be constructed and evaluated for understanding the exposure-response relationships of ocular ibuprofen or ketorolac with systemic caffeine in a rat experimental model of OIR. Model-based techniques will also be applied to facilitate the identification of the critical number of hyperoxic/hypoxic episodes resulting in abnormal angiogenesis in OIR. For Protocol 2, mechanism-based cellular PK/PD models will be developed to understand the influence of disease processes and drug effects in human retinal microvascular endothelial cells and astrocytes. Hyperoxia/hypoxia cycling and ibuprofen with or without caffeine concentrations will be linked to mathematical models of signal transduction (VEGF and Notch) and phenotypic outcomes. For Protocol 3, models developed from Protocols 1 and 2 will be scaled to inform and modify clinical protocols using translational modeling techniques developed within the core. Clinical data sets will be subsequently used to further refine clinical PK/PD models of retinopathy of prematurity (ROP) therapy using locally applied NSAIDS and systemic caffeine, better understand safety and efficacy, and provide a platform for the future individualization of ROP pharmacotherapy.

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 #
8473249
Study Section
Special Emphasis Panel (ZHD1-DSR-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$27,414
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Tu, Chengjian; Li, Jun; Shen, Shichen et al. (2016) Performance Investigation of Proteomic Identification by HCD/CID Fragmentations in Combination with High/Low-Resolution Detectors on a Tribrid, High-Field Orbitrap Instrument. PLoS One 11:e0160160
Beharry, Kay D; Valencia, Gloria B; Lazzaro, Douglas R et al. (2016) Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 40:189-202
Inayat, Musaddaq; Bany-Mohammed, Fayez; Valencia, Arwin et al. (2015) Antioxidants and Biomarkers of Oxidative Stress in Preterm Infants with Symptomatic Patent Ductus Arteriosus. Am J Perinatol 32:895-904
An, Bo; Zhang, Ming; Johnson, Robert W et al. (2015) Surfactant-aided precipitation/on-pellet-digestion (SOD) procedure provides robust and rapid sample preparation for reproducible, accurate and sensitive LC/MS quantification of therapeutic protein in plasma and tissues. Anal Chem 87:4023-9
Shen, Xiaomeng; Nair, Bindukumar; Mahajan, Supriya D et al. (2015) New Insights into the Disease Progression Control Mechanisms by Comparing Long-Term-Nonprogressors versus Normal-Progressors among HIV-1-Positive Patients Using an Ion Current-Based MS1 Proteomic Profiling. J Proteome Res 14:5225-39
Jivabhai Patel, Shamin; Bany-Mohammed, Fayez; McNally, Lois et al. (2015) Exogenous Superoxide Dismutase Mimetic Without Scavenging H2O2 Causes Photoreceptor Damage in a Rat Model for Oxygen-Induced Retinopathy. Invest Ophthalmol Vis Sci 56:1665-77
Tu, Chengjian; Beharry, Kay D; Shen, Xiaomeng et al. (2015) Proteomic profiling of the retinas in a neonatal rat model of oxygen-induced retinopathy with a reproducible ion-current-based MS1 approach. J Proteome Res 14:2109-20
Tu, Chengjian; Sheng, Quanhu; Li, Jun et al. (2015) Optimization of Search Engines and Postprocessing Approaches to Maximize Peptide and Protein Identification for High-Resolution Mass Data. J Proteome Res 14:4662-73
Kamisoglu, Kubra; Sukumaran, Siddharth; Nouri-Nigjeh, Eslam et al. (2015) Tandem analysis of transcriptome and proteome changes after a single dose of corticosteroid: a systems approach to liver function in pharmacogenomics. OMICS 19:80-91
Lott, Kaylen; Mukhopadhyay, Shreya; Li, Jun et al. (2015) Arginine methylation of DRBD18 differentially impacts its opposing effects on the trypanosome transcriptome. Nucleic Acids Res 43:5501-23

Showing the most recent 10 out of 32 publications