Defining physiological functions of syndecan-1 in health and disease using the syndecan-1 null mice
Inventors: Merton Bernfield, Pyong Park
Invention Types: Research Tool
Research Areas: Cardiovascular/Cardiology, Inflammation, Infectious Disease
Keywords: Animal Model (mouse)For More Information Contact: Khunkhun, Rajinder
Cell surface heparan sulfate proteoglycans (HSPG) bind to a wide variety of bioactive molecules and regulate a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, tumour metastasis, infection, and inflammation. Syndecan-1 is the major epithelial cell membrane HSPG in mammals. Dr. Pyong Park, PhD, from the Department of Respiratory Diseases, has developed a knock-out mouse by homologous recombination (mutation of exon 1 in a c57BL6 background) to study the physiological functions of syndecan-1 in health and in disease. Despite the variety of functional interactions that have been reported for syndecan-1 in cultured cells, Sdc1–/– mice are ostensibly normal and fertile.
Dr. Park has shown that newborn mice deficient in syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. He also found that a pathogenetic mechanism in which a host response to tissue injury, syndecan-1 shedding, is exploited to enhance microbial virulence apparently by modulating host defenses.
Additional work with the syndecan-1 knockout mice in tumorigenesis provided both genetic and biochemical evidence that syndecan-1 can modulate Wnt signalling, and is critical for Wnt-1–induced tumorigenesis of the mouse mammary gland. Further, recent studies indicate that syndecan-1 assures the correct functioning of inflammation by attenuating pro-inflammatory factors and facilitating the resolution of inflammation in a heparan sulfate-dependent manner.
The syndecan-1 knock-out mouse is thought to be a valuable research tool in defining:
• the underlying mechanisms of both physiological and pathological processes
• the precise functions of heparan sulfate proteoglycans and syndecan-1 in these mechanisms
These findings further suggest that syndecan-1 knock out mice can be used as a screening tool for drug development in:
• lipid metabolism
• wound repair
• epithelial barrier function
• cellular responses to growth factors, cytokines, chemokines, stress and proteinases
The syndecan-1 null mice is not commercially available and other syndecan-1 null mice have not been generated. The syndecan-1 null mice used currently around the world is derived from the line developed at Boston Children's Hospital.
• Non-exclusive license for research use
• Non-exclusive license for research tool distribution
• Collaboration or sponsored research
Key Publications: Park PW et al. Nature. 2001 May 3;411(6833):98; Alexander CM et al. Nature Genetics, 2000 July, Vol 25, p. 329.
Hayashida, K, Chen, Y, Bartlett, AH, and Park, PW, Syndecan-1 is an In Vivo Suppressor of Gram-positive Toxic Shock, J. Biol. Chem., 2008; 283: 19895-19903.
Hayashida, A, Bartlett, AH, Foster, TJ, and Park, PW, Staphylococcus aureus Beta-toxin Induces Acute Lung Injury through Syndecan-1, Am. J. Pathol., 2009; 174: 509-518.
Hayashida, K, Parks, WC, and Park, PW, Syndecan-1 Shedding Facilitates the Resolution of Neutrophilic Inflammation by Removing Sequestered CXC Chemokines, Blood, 2009; 114: 3033-3043.
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