Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with bioengineered vein-chip

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: JOHN P COOKE
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2022
Award: $665,322
Funding agency: National Heart Lung and Blood Institute

ABSTRACT
Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with
bioengineered Vein-Chip
Challenge: Increasing evidence shows that SARS-CoV-2, which is the novel coronavirus that causes COVID-
19, is able to trigger the formation of blood clots within the veins of patients. This ultimately manifests into strokes
and other life-threatening complications, being observed even in younger people. Related to that, is emerging
data that shows that the endothelial cells are dysfunctional across several organs other than the lungs of the
most severe COVID19 patients. These cells express the angiotensin-converting enzyme 2 (ACE2) receptor, to
which the virus attaches, using it as an entry point to infect cells. A recently created vein-on-a-chip (vein-chip)
that is an endothelialized organ-on-a-chip model incorporating the unique hemodynamics of the venous valve
cusp showed evidence that this model can be used to dissect the role of major determinants of venous
thrombosis – endothelium; hemodynamics; and blood components – together known as the Virchow's
triad. The central hypothesis in this proposal is that the venous thrombosis observed in COVID19 disease is due
to the interaction of the three determinants of thrombosis (Virchow's triad) – endotheliitis; complex
hemodynamics; and blood coagulability. There is an unmet need to understand the effects of the virus and/or
blood-borne inflammatory cytokines on the endothelium; and the interaction of these effects with the uniquely
complex venous hemodynamics (mechanotransduction); and to discover strategies to stabilize the endothelium
that may be co-operatively therapeutic with anticoagulants.
Proposal: The objective here is to deploy vein-chip technology to understand the determinants of SARS-CoV-
2 induced venous thrombosis; determine the roles of endothelial, hemodynamic and humoral alterations; and
propose therapeutic strategies. This objective will be met through three specific aims: Aim 1: Characterize the
SARS-CoV-2 induced endothelial dysfunction in the human Vein-Chip; Aim 2: Assess interplay of SARS-CoV-2
infection and hemodynamics in DVT with Vein-Chip, and Aim 3: Therapeutics-on-Chip: Assess
combinatorial therapeutics in infection-led DVT with Vein-Chip. The team driving this proposal is composed of
complementary expertise in vein-chip bioengineering and innovation (Jain); applying contemporary technology
in the molecular and computational biology of endothelial function and fate (Cooke); together with techniques to
define host response to coronaviral infection (Connor).
Impact: Taken together, the outcomes of this proposal will directly improve our understanding of thrombosis in
COVID-19 infection and make predictions that could potentially result in fast-tracking of therapeutic clinical trials.

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