PROJECT SUMMARY
Title: Platelet-hyaluronan interactions as regulators of inflammation and thrombosis
Key Words: Platelets, hyaluronan, inflammation, thrombosis, Hyaluronidase-2
The Candidate is a postdoctoral fellow and young investigator dedicated to developing an academic career
focused on investigating the intersection of inflammation and thrombosis through an extracellular matrix lens as
an underlying mechanism in chronic inflammatory disease. With a strong background in extracellular matrix
biology, and biochemistry, the candidate has developed new expertise in mechanistic platelet biology and the
use of mouse models to conduct the proposed studies. The Career Development Plan described in the proposal
outlines 2 years of mentored training including technical skill training and career development activities to
promote the successful transition to independence and future funding. The candidate's Mentor and Co-Mentor
have proven track-records of excellent, translational research productivity and successful mentorship. Research
Plan: Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of
modulating inflammatory and immune responses. These innate immune sensors continually survey their
environment and discriminate between homeostatic and danger signals. Components of the extracellular matrix
(ECM) are detected by platelets as `damage associated-molecular patterns' (DAMPS) and can elicit pro-
inflammatory responses. One such ECM component, the glycosaminoglycan hyaluronan (HA), acquires a unique
`cable-like' structure in response to inflammation. Our lab has shown that: (1) HA cable formation precedes
inflammatory cell infiltration, (2) HA cables produced by the endothelium recruit leukocytes, (3) Hyal-2 is required
for platelet biogenesis, and (4) the platelet-derived enzyme Hyal-2 degrades HA cables. Our preliminary
observations show that mice with systemic Hyal-2 deficiency display increased inflammation and disease
severity in a murine model of colitis. Importantly, these findings are significantly reduced by transfusion of wild-
type platelets. We believe that these results translate an entirely new mechanism by which platelet-HA
interactions regulate inflammation and will provide new insights into inflammatory pathways generalizable to
other inflammatory diseases. Based on our preliminary data we propose the overarching hypothesis that:
Dysregulation of vascular HA due to platelet Hyal-2 deficiency promotes inflammation and thrombosis.
We will evaluate the mechanism(s) by which platelet-hyaluronan interactions regulate inflammation, thrombosis,
and the underlying mechanism in which inflammation can alter megakaryocyte development and platelet
biogenesis by using a unique resource of patient-derived specimens and mouse models of inflammation. This
application builds on robust preliminary data, a personal track record of productive research, an extremely
supportive environment, an advisory panel with national recognition for their expertise in inflammation,
thrombosis, and translational research, and a fully committed department. Together these elements will support
and facilitate the training and advancement of the PI to a successful career of independent biomedical research.