Project 3 Update

AIM 1. This year we have completed and published the results of most of the proposed experiments within this aim (Blood 2014, ref. #4 below). We reported: 1) a role for Hyaluronidase 2 (HYAL2) and necessity for activation that allows platelets to cleave the HA -rich pathologic HA matrix; and 2) the discovery that patients with Inflammatory Bowel Disease (IBD) have greatly decreased levels of platelet HYAL2 (Blood 2014).

AIM 2. During investigation of this aim we realized that over-expression of HA and under-expression of HYAL2 leads to alterations in multiple aspects of hematopoesis, and in particular platelet formation. We have been investigating the role of hyaluronan in hematopeotic stem cell maturation within the bone marrow niche and ex-vivo.

AIM 3. This year we have reported that mice lacking hyaluronan synthase 3 (HAS3), but not those lacking HAS1, (deletion of HAS2 is embryonically lethal) are protected from bacterial colitis. HAS3 is important in generating HA in the microvasculature during inflammation, and the results implicate vasculature HA in extravasation during tissue injury. (International Journal of Cell Biology, ref. #7, below). In addition, we have begun looking at the activation of platelets by highly purified HA fragments.

We have had the following publications accepted this year with support from PEG funding, some of which cannot be listed in the Publications section because the PMCID has not yet been issued: 1. Petrey AC, de la Motte CA. Hyaluronan, a Crucial Regulator of Inflammation. Frontiers in Immunology 5:101. 2014. (2014) (PMCID:PMC3949149). 2. Nickerson KP, Homer CR, Kessler SP, Dixon LJ, Kabi A, Gordon IO, Johnson EE, de la Motte C, McDonald C. The dietary polysaccharide maltodextrin promotes Salmonella survival and mucosal colonization in mice. .PLoS One. 2014 9(7):e101789. eCollection 2014. (PMCID:PMC4084946). 3. Kaul A, Goparaju S, Dvorina N, Iida S, Keslar K, de la Motte C, Valujskik A, Fairchild R and Baldwin W. Acute and Chronic Rejection: Compartmentalization and Kinetics of Counterbalancing Signals in Cardiac Transplants. Am J Transplant. 15:333-45 (2015) (PMCID:PMC4304877); 4. Albeiroti S, Ayasoufi K, Hill DR, Shen B and de la Motte CA. Platelet hyaluronidase-2: an α-granule protein that translocates to the surface upon activation to function in extracellular matrix degradation. Blood 2014 ([Nov 19. pii: blood-2014-07-590513. Epub ahead of print]). 5. Lauer ME, Loftis J, de la Motte CA, Hascall VC. Analysis of the Heavy-Chain Modification and TSG-6 Activity in Pathological Hyaluronan Matrices. Methods Mol Biol. 1229:543-8. (2015); 6. Yuan H, Amin R, Ye X, de la Motte CA, Cowman MK. Determination of Hyaluronan Molecular Mass Distribution in Human Breast Milk. Analytical Biochemistry 2015. (Jan 8. pii: S0003-2697(15)00002-0. doi: 10.1016/j.ab.2014.12.020. [Epub ahead of print]). 7. Kessler SP, Obery DR and de la Motte C. Hyaluronan synthase 3 null mice exhibit decreased intestinal inflammation and tissue damage in the DSS-induced colitis model. Int. J. Cell Biol. 2015 (in press); 8. Scarpa M, Kessler S, Sadler T, West G, Homer C, McDonald C, de la Motte C, Fiocchi C, and Stylianou E. Interleukin-1α, an epithelial danger signal, is a potent activator of fibroblasts and reactivator of intestinal inflammation (Am. J. Path. –in press 2015); 9. Schuster AT, Homer CR, Kemp JR, Nickerson KP, Deutschman E, Kim Y, West G, Sadler T, Stylianou E, Krokowski D, Hatzoglou M, de la Motte C, Rubin BP, Fiocchi C, McDonald C, and Longworth MS. (2015) CAP-D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. Gastroenterology (in press); 10. de la Motte C and Kessler SP. The role of hyaluronan in innate defense responses of the intestine. Int. J Cell Biol 2015 (in press)

Trainees have benefitted immensely from the Skills Development and Resource cores of the PEG. Additionally, each trainee attended a National or International meeting where they presented their data from our supported PEG project. The chance to interact with established scientists was invaluable. Each of our trainees won poster/presentation/travel awards at their respective meetings (Proteoglycan Gordon Conference, American Gastroenterology Association, Experimental Biology, American Society of Clinical Chemistry) indicating that they represented our laboratory and the PEG very well.

In addition to publication, meetings with presentations: Experimental Biology 2014 (San Diego); American Gastroenterology Association Annual Meeting 2014 (Chicago); Proteoglycan Gordon Conference 2014 (Andover, NH); Matrix Biology Meeting 2014 (Cleveland)

Our plans include three distinct lines of investigation. First, we will continue delving into the role that HA matrices play in modulating platelet formation from megakaryocytes in vivo and in vitro. We will also further investigate the role of HA and HYALs in additional hematopoetic cell development, which we have determined to be dysregulated in HYAL2 deficient mice. (Aim 2)

Second, we will continue to investigate non-HYAL2 mechanisms through which pathologic HA matrices are specifically degraded using human colon tissue, mouse models of colitis and in vivo primary human intestinal cells. To this end we have recently identified a protein we had not previously suspected in HA degradation, KIAA1199. We plan to continue investigating KIAA1199’s role in platelet mediated HA degradation, as well as other intestinal cell types. (this is a new avenue and an extension of AIM 1).

Third, we will continue to investigate the activation of platelets and monocytes by HA fragments, both purified and those produced by degradation of the inflammatory HA matrix.

1. Petrey AC, de la Motte CA. Hyaluronan, a Crucial Regulator of Inflammation. Frontiers in Immunology 5:101. 2014. (2014) (PMCID:PMC3949149)

2. Nickerson KP, Homer CR, Kessler SP, Dixon LJ, Kabi A, Gordon IO, Johnson EE, de la Motte CA, McDonald C. The dietary polysaccharide maltodextrin promotes Salmonella survival and mucosal colonization in mice. .PLoS One. 2014 Jul 7;9(7):e101789. eCollection 2014. ( PMCID:PMC4084946)

3. Kaul A, Goparaju S, Dvorina N, Iida S, Keslar K, de la Motte C, Valujskik A, Fairchild R and Baldwin W. Acute and Chronic Rejection: Compartmentalization and Kinetics of Counterbalancing Signals in Cardiac Transplants. Am J Transplant. 15:333-45 (2015) (PMCID:PMC4304877)

 
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