A multiorgan microphysiological platform to discover and screen therapeutics for treating radiation induced vascular injury

About This Grant

Summary In the event of a nuclear or radiological catastrophe, affected individuals are exposed to a wide range of radiation doses with the extent of injury depending on the victims' distance from the epicenter, the duration of exposure, and their inherent sensitivity/resistance to ionizing radiation, amongst other factors. While the use of Neupogen, Neulasta and Entolimod to treat hematopoietic acute radiation syndrome (H-ARS) has been approved by the FDA, therapeutic approaches to the treatment of radiation-induced vascular/endothelial injury are largely supportive. Vascular/endothelial injury is a leading cause of morbidity and mortality in radiation-induced injury through damage to vascular barrier function and increased leukocyte trafficking and there are no specific pharmacologic therapies available that protect from leukocyte- mediated tissue damage. While animal models have been used to develop therapeutics for treating radiation damage, use of emerging technologies such as organ-on-chip allows for testing of these therapeutics in biomimetic environments using primary human cells. We propose to integrate our microfluidic models of blood-brain barrier (BBB), gut, and lung into a multiorgan RadChip platform that incorporates essential features for testing radiation induced vascular injury. We will characterize the impact of radiation damage on vascular endothelial cell activation, barrier integrity, transendothelial electrical resistance (TEER) and interaction with immune cells in our RadChip composed of multiple important organ-specific cell types. The signaling pathways regulating radiation-induced vascular permeability and leukocyte migration in human EC will be determined. A novel in silico model will be used to elucidate cellular processes impacted by radiation exposure and identify/validate FDA-approved drugs/compounds as potential therapeutics for treating radiation injury. This multiorgan RadChip will be used to test the efficacy of FDA approved drugs for treating radiation induced vascular injury. The specific aims of this project are to 1) Use a multiorgan platform to model radiation-induced vascular injury in humans, 2) Determine the mechanism by which radiation injury impacts immune cell-endothelial cell interaction, 3) Use a novel in silico model to determine the signaling pathways regulating radiation-induced vascular damage to repurpose FDA approved therapeutics. These studies will not only provide important mechanistic insights into the underlying pathogenesis of acute radiation syndrome but also provide a platform to identify and screen potential FDA-approved drugs/compounds for treating radiation injury.