instmctions): (Project 3, de la Motte) Platelet Production and Modification of Inflammmatory HA Fragments in Colitis - The glycan-rlch extracellular matrix (ECM) is a commonly overlooked element in the investigation of inflammation. However, an increasing body of evidence implicates ECM, especially hyaluronan (HA) as a dynamic participant in the immune cell microenvironment. HA fragments are gaining attention as 'endogenous danger signals'that regulate Innate Immune responses and frequently promote inflammation. Yet specific mechanisms that create fragments in the cellular environment in sufficient quantity to mediate responses have not been defined. We have evidence that platelets produce HA fragments in extracellular environments by two mechanisms: 1) cleavage of HA from the surface of activated, small vessel endothelium by means of their surface hyaluronidase, HYAL2;and 2) extrusion of endogenous, internal HA during activation. We hypothesize that platelets, by generating signaling sized HA fragments, exacerbate and perpetuate inflammation. First, we propose to identify the cascade of cellular events that lead platelets to cleave HA fragments from endothelial cell surfaces, to biochemically characterize the HA liberated, and to test whether interruption of this cascade will impact inflammation in a mouse model of colitis. Second, we propose to determine the source of HA in platelets and the cellular mechanism that releases it, to biochemically characterize this endogenous HA, and to test whether deletion of platelet HA affects inflammation in the in vivo colitis model. Third, we propose to test whether HA fragments produced by platelet HYAL2 clipping, or HA fragments released by platelets during degranulation, or commercial purified HA of similar sizes to platelet created fragments will activate monocytes and platelets themselves. Ultimately these studies will define two new, glycan-mediated mechanisms whereby platelets contribute to inflammation, an area of great clinical interest pertaining to many diseases Including IBD. The data will likely show an organized pathway through which the ECM, after modification by platelets, contributes to inflammatory responses.
Platelets, in addition playing a central role in coagulation, are recognized as mediators of inflammation. We propose that platelets, by producing pro-inflammatory HA fragments, contribute to a cycle of inflammation within the microvasculature that exacerbates and perpetuates chronic inflammatory diseases, such as inflammatory bowel disease.
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