Assessment and Mechanisms of Blood Vessel Dysfunction in Critically Ill Children

Key Words: Capillary Leak, Endothelial Dysfunction, Single Cell RNA Sequencing, Translational Research

The objectives of this proposal are to develop better assessments and understanding of blood vessel function in critically ill children. Blood vessels are continuously lined by endothelial cells that regulate intravascular volume and nutrient exchange to organs. Most important is the capillary blood vessel segment, due to its large cumulative surface area. In critical illness, the capillary barrier becomes disrupted and intravascular fluid leaks into the extravascular space, contributing to shock, organ dysfunction and if not addressed, death. Currently, there is no way to assess leak to help clinicians to identify patients at risk or to evaluate treatment regimens, complicating care in the sickest children. Furthermore, a better understanding of EC changes that induce capillary leak can aid in developing new therapies. To improve the care of critically ill children, I aim to develop a bedside assessment of capillary leak using retinal fluorescein angiography and analyze the EC transcriptome by single cell RNAseq of ECs isolated from discarded guide wires removed from critically ill compared to non-critically ill children and normal surgical specimens to identify significantly different gene products that can be evaluated for causality by electrical cell-substrate impedance sensing in an established in vitro model of human capillary barrier function. My research will take place in my laboratory within the Yale Vascular Biology and Therapeutics Program and in conjunction with my position at Yale-New Haven Children’s Hospital. This environment features researchers and mentors in pediatric critical care medicine and in vascular biology and immunology. Yale’s infrastructure and supportive environment can facilitate the successful completion of this project. Through this proposal, I hope to make discoveries that will immediately direct treatment decisions in critically ill children and ultimately discover new therapies for vascular leak.