PIs: Yoram Vodovotz, PhD
Co-PIs: Gregory M. Constantine, PhD (Pitt—Mathematics); Steve Chang (CEO of Immunetrics); Drs. Gary Nieman and Kris Maier (SUNY-Syracuse)
Title: Mathematical Modeling of Inflammation in ARDS
Description: Trauma and systemic infection elicit an acute inflammatory response. Inflammation involves complex interactions among leukocytes, their products (cytokines, free radicals, and proteases), and the tissue damage/dysfunction that ensues. This multiple organ dysfunction often manifests as septic shock and severe lung dysfunction, referred to collectively as the acute respiratory distress syndrome (ARDS), and contributes to the 215,000 annual deaths in the U.S. from sepsis. The complexity of this process has stymied the progress towards immunomodulatory ARDS therapeutics. We have developed a mathematical model of these elements in order to unravel this complex interplay in various settings of acute inflammation, and have calibrated distinct variants of this model with data from mice, rats, swine, and humans (University of Pittsburgh Inflammatory Analyte/Modeling Component). Our modeling platform has been used to gain both basic and translational insights, the latter including simulated (in silico) clinical trials. In conjunction with these efforts, we developed a sepsis + gut ischemia/reperfusion (Sepsis+I/R) porcine model that mimics the pathogenesis of human septic shock and ARDS (Upstate Medical University ARDS Animal Model Component). We hypothesize that mathematical analysis of the complex biochemical and physiologic data generated in our Sepsis+I/R model will enable us to isolate key therapeutic targets and to test novel therapeutics; one such agent is the modified tetracycline COL-3. Our Specific Aims are: 1) to develop a robust mathematical model describing Sepsis+I/R-induced shock and ARDS in swine, its pathologic consequences, and possible therapies, 2) to utilize COL-3 as a tool to further calibrate the mathematical model and 3) to demonstrate that NE, MMP-2 and MMP-9 are critical components in Sepsis+I/R-induced septic shock and ARDS pathogenesis. Our calibrated mathematical model will be used to conduct in silico clinical trials and establish a platform for the rational development of novel ARDS therapeutics. The in silico trials will be validated in animal experiments. The proposed translational studies will develop a robust mathematical model capable of describing the complex pathogenesis of sepsis-induced ARDS and identify target molecules whose modulation would significantly improve clinical outcome.
Source: NIH (National Heart, Lung and Blood Institute)
Amount: $1, 354,646