A condition with no cure, inflammatory Bowel Disease (IBD) affects ~3 million patients in the US each year with
the number ever increasing. IBD consists of two closely related disorders, Crohn’s disease (CD) and ulcerative
colitis (UC), and usually manifest in the first three decades of life leading to relentless inflammatory destruction
of the gastrointestinal tract in susceptible individuals. The blood of IBD patients exists in a hypercoagulable state
and thromboembolism (TE), in which life-threatening blood clots break off and travel through the blood stream
to block other vessels, is the most significant cause of mortality in IBD. This increased risk is between 3- and 15-
fold during inactive and active disease respectively. Necropsy studies report thrombosis affects up to 40% of
IBD patients, and 25% of patients suffering a thrombotic event have a fatal outcome. Current treatment regimens
do not address thrombosis risk, and widespread steroid use increases risk. In addition to their classical role in
hemostasis, platelets have emerged as novel regulators of the immune response that act as significant drivers
of inflammation and tissue damage. Clinical reports suggest that platelet abnormalities associate with IBD
activity, severity, and thrombosis risk, however molecular pathways responsible for increased platelet
reactivity and thrombosis in IBD are not well studied. This proposal tests the significant and innovative
hypothesis that platelets become transcriptionally altered toward hyperactivation in IBD and identified
the C-type lectin layilin as a novel regulator of platelet activation and thrombosis. We will employ
complementary clinical, in vitro, and in vivo approaches, a unique resource of patient tissues and expertise with
human platelets and microvascular endothelial cells, along with state-of-the-art sequencing techniques,
CRISPR/Cas9 technology, and intravital microscopy to rigorously test this hypothesis. Specific Aim 1 will
determine how regulators of platelet activation, including layilin, are altered during active and inactive disease in
IBD and contribute to disease outcomes. Specific Aim 2 will determine how layilin regulates platelet activation,
define downstream activation pathways, and identify receptors and ligands mediating platelet adhesion to novel,
inflammatory hyaluronan-cable matrices. Specific Aim 3 will establish how targeting pathways downstream of
layilin in platelets improves inflammation and thrombosis during colitis. Successful completion of these aims will
1) determine how transcriptional changes in platelets contribute to inflammation and thrombosis in IBD, 2)
determine downstream regulators of platelet activation mediated by layilin, 3) establish whether targeting
dysregulated platelet activation pathways in improves inflammation and thrombosis in murine colitis. Data
generated in this proposal will significantly increase our understanding of how the hyperreactive platelets
contribute to the pathophysiology of IBD.