Ongoing studies on the structure and function of endothelial heparan sulfate proteoglycans focus on the development of mutant mice bearing endothelial specific mutations in glycosaminoglycan assembly. Both loss of function and gain of function mutations have been identified that impact angiogenesis and inflammation. Methods have been developed to identify the repertoire of proteins on the surface of endothelial cells that interact with and depend on heparan sulfate. Proteins under study include C-type lectins and neuropilins.
We have an ongoing interest in the role of proteoglycans in microbial infection and sepsis. These studies are part of a collaboration with Victor Nizet’s lab and funded through Program Project Grants. Current studies focus on the importance of particular proteoglycans or modifications of the heparan sulfate chains for bacterial adherence and invasion, neutrophil and platelet killing, and neutrophil function. A better understanding of the role of proteoglycans involved in these processes might define molecular targets for therapeutic intervention.
Gordts, P.L.S.M., Foley, E., Lawrence, R., Sinha, R., Lameda-Diaz, C., Deng,, L., Nock, R. Glass, C.K., Erbilgin, A., Lusis, A.J., Witztum, J.L., and Esko, J.D. (2014) Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced Type I interferon signaling. Cell Metab. 20, 813–826. Highlighted in: N. R. Gough (2014) Heparan sulfate proteoglycans control basal inflammation. Sci. Signal. 7, ec320.
Ge, X.N., Ha, S.G., Rao, A., Greenberg, Y.G., Rushdi, M.N., Esko, J.D., Rao, S.P., and Sriramarao, P. (2014) Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model. Glycobiology 24:715-727
Doody, K.M., Stanford, S.M., Sacchetti, C.D., Svensson, M.N., Coles, C.H., Mitakidis, N., Kiosses, W.B., Bartok, B., Fos, C., Cory, E., Sah, R.L., Liu-Bryan, R., Boyle, D.L., Arnett, H.A., Mustelin, T., Corr, M., Esko, J.D., Tremblay, M.L., Firestein, G.S., Aricescu, A.R. and Bottini, N. (2015) Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci. Transl. Med. 7:288. Awarded 2016 Lee C. Howley Sr. Prize for Arthritis Scientific Research, Arthritis Foundation.
Xu, D., Olson, J., Cole, J.N., van Wijk, X.M., Brinkmann, V., Zychlinsky, A., Nizet, V., Esko, J.D., and Chang, Y.C. (2015) Heparan sulfate modulates neutrophil and endothelial function in antibacterial innate immunity. Infect Immun. 83:3648-3656.
van Wijk, X.M., Döhrmann, S., Hallström, B.M., Li, S., Voldborg, B.G., Meng, B.X., McKee, K.K., van Kuppevelt, T.H., Yurchenco, P.D., Palsson, B.O., Lewis, N.E., Nizet, V. and Esko, J.D. (2017) Whole genome sequencing of invasion-resistant cells identifies laminin a2 as a host factor for bacterial invasion. MBio 8:e02128-16.