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Aaron C. Petrey, Ph.D.

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Academic Information

Departments: Pathology - Assistant Professor

Divisions: Microbiology and Immunology

Academic Office Information

Aaron.Petrey@u2m2.utah.edu

(801) 213-2064

George and Dolores Eccles Institute of Human Genetics

15 N 2030 E, Room: 4250A
Salt Lake City, UT 84112

My research focuses on platelets as effector cells capable of mediating inflammation through interactions with immune and non-immune cells. These studies uncovered a novel mechanism in inflammatory bowel disease (IBD) whereby platelet interactions with the glycan hyaluronan (HA) regulate immune cell recruitment and inflammation in the intestinal microvasculature. Using mouse models, biochemical assays, tissue and primary cells from IBD patients, we have determined that platelet hyaluronidase-2 regulates the early stages of disease progression by degrading hyaluronan on the surface of the microvasculature. Unexpectedly, this pathway is dysregulated in endothelial cells subject to viral mimetics, in murine models of influenza, and in platelets isolated from patients with IBD, COVID-19 or clinical sepsis.

Under normal physiological conditions, a dynamic, glycan-rich matrix comprised of HA and other glycoconjugates lines the vascular endothelium and restricts inflammatory cell access. However, in the context of tissue damage or infection, HA may become covalently modified with the heavy chains (HC) of serum inter-α-inhibitor to form a biologically distinct HA-HC complex. This novel pathological form of HA is pro-inflammatory, highly adhesive for naïve leukocytes and platelets. However, when degraded from the endothelial surface, HA functions as a unique damage-associated molecular pattern at the interface of inflammation and coagulation. My research seeks to understand the how the interplay between leukocyte and platelet interactions with HA at the endothelial surface contributes to human disease. Our data suggests that fragments of HA released during infection and inflammation can sustain microvascular dysfunction and cytokine release triggering a proinflammatory feedback loop that results in microvascular thrombosis.

Research Statement

My research focuses on platelets and megakaryocytes as effector cells capable of mediating inflammation through interactions with immune and non-immune cells. These studies focus on the extracellular matrix glycosaminoglycan hyaluronan (HA) as a key molecule that modulates innate immune mechanisms which when dysregulated can lead to disease. My work recently uncovered a novel mechanism in inflammatory bowel disease (IBD) whereby platelet interactions with HA regulate immune cell recruitment and inflammation in the intestinal microvasculature. Using mouse models, biochemical assays, tissue and primary cells from IBD patients, these studies provide evidence that platelet hyaluronidase-2 regulates the early stages of disease progression by degradation of a unique form of HA present on the surface of the inflamed intestinal microvasculature. Unexpectedly, this pathway becomes dysregulated in IBD patients and in murine models of colitis.

Under normal physiological conditions, a dynamic, glycan-rich matrix comprised of HA and other glycoconjugates lines the vascular endothelium and restricts inflammatory cell access. However, in the context of tissue damage or infection, HA may become covalently modified with the heavy chains (HC) of serum inter-α-inhibitor to form a biologically distinct HA-HC complex that can be observed as “cable-like” structures. This novel pathological form of HA is pro-inflammatory, highly adhesive for naïve leukocytes and platelets, and functions as a unique damage-associated molecular pattern at the interface of inflammation and coagulation. My research seeks to understand how this novel matrix is regulated, how HA-HC controls leukocyte and platelet responses, define the receptor(s) that mediate recognition and activation, and determine the signaling pathways regulated by HA-HC.

Altered platelet function is a hallmark of many inflammatory sates, and my work examines the hypothesis that in chronic inflammatory disease states, such as in IBD, platelets (and other hematopoietic cells) are ‘born’ dysregulated due to alterations within the bone marrow microenvironment which lead to dysregulation of protective mechanisms and acquisition of pro-inflammatory features. My research provides evidence that HA-HC accumulates within the bone marrow during inflammation and contributes to altered megakaryocyte and myeloid development. These preliminary studies have led to the identification a HA receptor with previously unknown roles regulating hematopoiesis and inflammation.