PROJECT SUMMARY/ABSTRACT
Sepsis is a critical illness arising from dysregulated host response to infection where invading pathogens elicit
an adverse systemic inflammatory response that affects multiple organs and tissues. Currently, there are limited
therapies that effectively treat this disease. The overarching goal of our work is to identify new molecular targets
that can potentially serve as diagnostics or therapeutics for prevention and treatment of sepsis. This project
focuses on glycocalyx shedding as not merely a consequence, but a critical cause, of inflammatory injury.
Specifically, we hypothesize that bacterial infection promotes disintegrin metalloprotease (ADAM) upregulation
and activity to shed glycocalyx molecules on endothelial surface and release their fragments into the circulation,
which act as inflammatory signals to mediate microcirculatory dysfunction and barrier leakage by triggering
endothelial cytoskeleton-junction responses. This novel concept will be tested by completing two aims: Aim 1 to
characterize the molecular property of glycocalyx shedding products and function in microvascular inflammation
during sepsis; Aim 2 to elucidate the molecular mechanisms of endothelial glycocalyx shedding and barrier injury.
We propose a multifaceted approach based on an innovative design that integrates peptidomics, proteomics and
nanotechnology with multispectral photoacoustic tomography, super-resolution confocal and 3D intravital
microscopic imaging. Functionally viable human lungs and microvessels serve as the primary models, which are
complemented by animal models and cell experiments. Microvascular barrier structure and function will be
examined in-depth at the organ, tissue and cell levels under pathophysiologically relevant conditions of bacterial
infection. We expect to gain novel insights that will not only fill the knowledge gaps in understanding the
molecular mechanisms of septic injury, but also contribute to the development of effective therapeutics against
infectious diseases. The proposed human organ studies further highlight the translational values of our work.