Many have never heard of O-glycans. But without it, you probably wouldn’t be alive.
O-glycans are a sugar that your body makes, and are the focus of my research. In my lab, we’ve found O-glycans are important in the development of the lymphatic system, which moves fat and fatty acids throughout the body. Without this sugar, the body doesn’t know if it should grow blood vessels or pieces of the lymphatic system or how to connect them properly. This can lead to fatty liver disease, a condition that affects as much as one-quarter of the world’s population and can lead to liver inflammation, cirrhosis and liver cancer.
My lab is also studying how lymphatic drainage can be used in the diagnosis and treatment of cancer. The lymphatic system is responsible for carrying cancerous cells between various parts of the body in a process called metastasis. We are now working to understand how to prevent these potentially deadly conditions.
In patients with colitis and colorectal tumors, we’ve found that O-glycans are different than in those with normal intestinal systems. There’s a chance a lack of this sugar in the intestines might cause these diseases. So we’re also exploring this hypothesis—in hopes of using the knowledge we gain to treat intestinal diseases.
O-glycosylation is increasingly appreciated as having a wide and yet largely unexplored spectrum of biological functions. Altered expression of mucin-type O-linked oligosaccharides (O-glycans) has been associated with tumor development and autoimmune diseases. Our research centers on functions of O-glycans in health and disease using gene-targeted mice as models.
Many membrane and secreted proteins are modified by O-glycans. The main O-glycan forms are core 1– and core 3–derived structures that are expressed primarily in endothelial, epithelial, and hematopoietic cells. Biosynthesis of core 1– and core 3–derived O-glycans is controlled, respectively, by the core 1 b1,3-galactosyltransferase (T-synthase) and core 3 b1,4-N-acetylglucosaminyltransferase (C3GnT).
To investigate O-glycan functions, we generated mice with global, tissue-specific, or inducible deficiencies in T-synthase and/or C3GnT. Our main goals are to: a) investigate biological functions of protein O-glycosylation in endothelial cells, epithelial cells, and hematopoietic cells, and b) determine mechanisms by which O-glycans regulate vascular development, inflammation, and tumorigenesis.
Current focuses are primarily on O-glycans in lymphangiogenesis and intestinal disease, two areas developed in my lab with high human disease relevance. We demonstrated that endothelial O-glycans regulate the O-glycoprotein podoplanin to control the separation of blood and lymphatic systems during embryonic and postnatal development. We are determining how podoplanin regulates lymphangiogenesis. Intestinal O-glycan expression is frequently altered in patients with colitis and colorectal tumors, which plays an unknown etiological role. We found that mice lacking intestinal O-glycans have impaired intestinal mucus barrier function and develop spontaneous colitis and colorectal tumors, supporting a causal role for abnormal O-glycans in the pathogenesis of these intestinal diseases. We are investigating mechanisms underlying this pathology. Many tumors metastasize via lymphatics in the absence of functional intratumor lymphatics. We will use mouse tumor models, including our colorectal tumor mouse model, to test the role of aberrant lymphangiogenesis in tumor metastasis. This direction synergizes our strengths in lymphangiogenesis and intestinal disease. Integrating data from these studies will provide a broad view of O-glycosylation function in health and disease.
M.D., Binzhou Medical College, China, 1982
M.S., Qingdao University Medical College, China, 1990
Ph.D., Soochow University Medical College, China, 1995
Honors and Awards
2003 Scientist Development Award, American Heart Association
2006 Scientific Consultant, American Stem Cell, Inc., CA
2007 Merrick Award for Outstanding Research, Oklahoma Medical Research Foundation
2009 Merrick Foundation Distinguished Scientist, Oklahoma Medical Research Foundation
2012 Edward L. and Thelma Gaylord Prize for Scientific Achievement
American Society of Hematology
Member, Society for Glycobiology
Joined OMRF Scientific Staff in 2002.
Kondo Y, Fu J, Wang H, Hoover C, McDaniel JM, Steet R, Patra D, Song J, Pollard L, Cathey S, Yago T, Wiley G, Macwana S, Guthridge J, McGee S, Li S, Griffin C, Furukawa K, James JA, Ruan C, McEver RP, Wierenga KJ, Gaffney PM, Xia L. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight. 2018 Jul 26;3(14). pii: 121596. PMCID: PMC6124414
Zhou L, Jiang M, Shen H, You T, Ding Z, Cui Q, Ma Z, Yang F, Xie Z, Shi H, Su J, Cao L, Lin J, Yin J, Dai L, Wang H, Wang Z, Yu Z, Ruan C, Xia L. Clinical and Molecular Insights into Glanzmann's Thrombasthenia in China. Clin Genet. 2018 Aug;94(2):213-20. PMCID: PMC6041146
Ghafoory S, Varshney R, Robison T, Kouzbari K, Woolington S, Murphy B, Xia L, Ahamed J. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury. Blood Adv. 2018 Mar 13; 2(5):470-80. PMCID: PMC5851416
Li Y, Fu J, Ling Y, Yago T, McDaniel JM, Song J, Bai X, Kondo Y, Qin Y, Hoover C, McGee S, Shao B, Liu Z, Sonon R, Azadi P, Marth JD, McEver RP, Ruan C, Xia L. Sialylation on O-glycans protects platelets from clearance by liver Kupffer cells. Proc Natl Acad Sci USA. 2017 Aug 1;114(31):8360-5. PMCID:PMC5547648
Bergstrom K, Liu X, Zhao Y, Gao N, Wu Q, Song K, Cui Yi, Li Y, McDaniel JM, McGee S, Chen W, Huycke MM, Houchen CW, Zenewicz LA, West CM, Chen H, Braun J, Fu J, Xia L*. Defective intestinal mucin-type O-glycosylation causes spontaneous colitis-associated cancer in mice. Gastroenterology. 2016 July;15:152-64. PMCID:PMC5068133
Pan Y, Yago T, Fu J. Herzog B, McDaniel JM, Padmaja Mehta-D’souza, Cai X, Ruan C, McEver RP, West C, Dai K, Chen H, Xia L. Podoplanin requires sialylated O-glycans for stable expression on lymphatic endothelial cells and for interaction with platelets. Blood. 2014 Dec 4;124(24):3656-65. PMCID: PMC4256915
Herzog BH, Fu J, Wilson SJ, Hess PR, Sen A, McDaniel JM, Pan Y, Sheng M, Yago T, Silasi-Mansat R, McGee S, May F, Nieswandt B, Morris AJ, Lupu F, Coughlin SR, McEver RP, Chen H, Kahn ML, Xia L. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature. 2013 Oct3;502(7469):105-9. PMCID: PMC3791160
Fu J, Wei B, Wen T, Johansson ME, Liu X, Bradford E, Thomsson KA, McGee S, Mansour L, Tong M, McDaniel JM, Sferra TJ, Turner J, Chen H, Hansson GC, Braun J, Xia L. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. 2011 Apr;121(4):1657-66. PMCID: PMC3069788
Yago T, Fu J, McDaniel JM, Miner JJ, McEver RP, Xia L. Core 1-derived O-glycans are essential E-selectin ligands on neutrophils. Proc Natl Acad Sci USA. 2010 May 18;107(20):9204-9. PMCID: PMC2889084
Cardiovascular Biology Research Program, MS 45
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7892
Lab: (405) 271-3979
Fax: (405) 271-3137
Jianxin Fu, M.D., Ph.D.
Research Assistant Member
Kirk Bergstrom, Ph.D.
Research Assistant Member
Yuji Kondo, Ph.D.
Research Assistant Member
Jane Song, Ph.D.
Assistant Staff Scientist
Dylan Shan, Ph.D.
John Michael McDaniel
Senior Laboratory Manager
Senior Research Assistant
Senior Research Technician
Administrative Assistant IV