Project Summary/Abstract
Arterial thrombosis, which describes the formation of abnormal blood clots in the artery, is a highly fatal
disease that claims ~500,000 American lives per year. A symbolic feature of arterial thrombosis is the elevated
shear rate and shear force generated by stenosis, which facilitates platelet aggregation towards vessel
occlusion. Unfortunately, current therapeutic strategies are ineffective in inhibiting the prothrombotic effects of
the pathological blood flow, and have a major risk of excessive bleeding. The overall objective of this proposal
is to establish a mechanism-driven strategy to better treat arterial thrombosis. Our lab's previous works and my
research identified that the prothrombotic effects of pathological blood flow result from a phenomenon called
“biomechanical platelet aggregation”, in which mechanical force drives platelets to crosslink. Von Willebrand
factor (VWF) is a plasma protein that mediates platelet crosslinking by binding to platelet receptor GPIbα. In
my preliminary study, I worked on an artificially designed triple-residue VWF mutation named `M13', which
inhibited VWF in mediating biomechanical platelet aggregation and shear-induced thrombogenesis, but did not
affect platelet adhesion or hemostasis. Based on these findings, I hypothesize that: biomechanical platelet
aggregation is a key factor to arterial thrombosis, and its inhibition can suppress arterial thrombosis
without compromising hemostasis. I propose 4 aims to step-by-step establish anti-thrombotic approaches
targeting the biomechanical platelet aggregation. Aim 1 will combine biomechanics and hematology assays to
study the mechanism underlying M13's function in inhibiting biomechanical platelet aggregation but not
adhesion. Aim 2 will establish a microfluidic-based assay that concurrently assesses platelet adhesion and
shear-induced thrombogenesis, which allows the screening of anti-thrombotics targeting biomechanical platelet
aggregation. In Aim 3, a monoclonal antibody against VWF, NMC4, was identified to be functionally aligned
with my anti-thrombotic strategy. I will collaborate with my postdoctoral lab and use NMC4 as a prototype to
design and produce anti-thrombotic agents. A 3-step screening procedure will be established to select
candidate agents with the best functional performance. Lastly in Aim 4, I will expand my anti-thrombotic
strategy to another platelet receptor also important to biomechanical platelet aggregation: integrin αIIbβ3. I will
explore the efficacy and safety of inhibiting both VWF- and αIIbβ3-mediated biomechanical platelet aggregation
in treating arterial thrombosis exacerbated by diabetes. Overall, this research will be accomplished in the
setting of a comprehensive career development program designed to help me achieve my career goal as an
independent researcher in the interdisciplinary field of vascular biology, mechanobiology and bioengineering.
During the K99 phase, I will continue to gain expertise in biochemical, preclinical and translational approaches.
My mentor, collaborators and consultants will together guide me in the steps towards successful transition to
independence over the course of the award period.
