Inflammation and sepsis is characterized by dysregulated host responses that span hemostatic, inflammatory, and immune continuums. Thrombosis is a common complication of sepsis, contributing to adverse outcomes including organ failure and death. The significance of this devastating dysregulated host response is demonstrated by data suggesting half of all hospital deaths, including the Veterans population, may be attributed to sepsis. Emerging evidence supports the concept that dysregulated platelet responses mediate the pathophysiology during inflammation. Nevertheless, the molecular mechanisms and functional consequences of dysregulated platelet functions during sepsis remain incompletely understood. Our proposal, entitled ?Platelet Reprograming During Inflammation? will identify new pathways by which inflammatory agonists including, interferons (IFNs) regulate gene expression in platelets and their parent cell, the megakaryocyte (MK). Our preliminary studies have identified that the expression of interferon-induced transmembrane protein 3 (IFITM3) is robustly induced in human platelets during sepsis. Moreover, our data demonstrate that IFITM3 upregulates fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. The regulation and function IFITM3 in MKs and platelets, or for that matter any other human cell, has never previously been identified. In this proposal, we will leverage prospective clinical studies in sepsis with in vitro and in vivo murine models. These complementary human and murine studies will allow us to demonstrate clinical relevance while also dissecting the mechanisms by which IFITM3 governs MK and platelet function during inflammation. These studies are translational and innovative as IFITM3 regulation of endocytosis, a process critical for cellular function. This has not previously been studied in MKs, platelets, or ? for that matter - primary human cells. They will also determine for the first time whether inflammatory agonists regulate transcriptional and translational events in MKs and developing platelets. This work will test an important functional hypothesis and clarify pathophysiologic mechanisms of thrombosis during inflammation and sepsis. This proposal has both immediate translational potential for the thousands of Veterans estimated to develop sepsis, and will underlie additional progress for inflammatory diseases more broadly affecting the Veteran population.

Public Health Relevance

Thrombosis, or blood clots, commonly complicates inflammatory syndromes and may contribute to organ failure and death in Veterans. Small circulating cells in the body, called platelets, mediate blood clotting during sepsis. We will examine how infection changes platelets and causes dysregulated blood clotting.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX001696-02
Application #
9740920
Study Section
Hematology (HEMA)
Project Start
2018-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148