Chen funded $1.9 million for sepsis research

CFRI researcher Guoyun Chen, MD, PhD, has been awarded $1.9 million from the National Institutes of Health to fund his research project, titled “Targeting Siglec -9/E for therapy of sepsis”. The funded studies will build on Chen’s prior work investigating the function of Siglecs in innate immune and inflammatory responses, with the ultimate aim of identifying novel targets for sepsis therapy. 

Sepsis is a complex syndrome, but can be broadly defined as an extreme, dysregulated inflammatory host response to infection. Sepsis is a significant public health issue: each year in the United States alone, more than 1.5 million cases of sepsis are reported, and 250,000 deaths are attributed to this condition1 . Despite the availability of treatment with antibiotic therapy, inotropes, fluid resuscitation and end-organ support, there is a critical need for identification of additional druggable targets for effective therapy.

Chen’s experimental approach centers on investigating the negative regulation of toll-like receptor (TLR) signaling. TLR signaling is a key pathway in sepsis pathogenesis, and is responsible for much of the excessive inflammatory response. As many infectious agents express ligands for several TLRs, current therapies targeting individual receptors have proven ineffective.

Chen’s innovative work aims to overcome these therapeutic limitations by simultaneously targeting multiple TLRs and dampening their downstream inflammatory signaling. Previously published data from the Chen Laboratory identified members of the sialic acid-binding immunoglobulin superfamily (Siglecs) as potential candidates for sepsis therapy. Studies using dendritic cells deficient in Siglec-E displayed increased inflammatory responses to all TLR ligands tested compared to cells containing Siglec-E. New preliminary experimental results suggest that Siglec-E negatively regulates all TLR4 by inducing TLR endocytosis and degradation, thereby terminating signaling downstream. With the NIH award, the Chen laboratory will now further study the mechanism by which this occurs and will explore novel therapeutic strategies using Siglec-E as a candidate for sepsis therapy.

Dr. Chen holds the position of Assistant Professor in the Department of Pediatrics at UTHSC.

¹Centers for Disease Control and Prevention. Data & Reports Sepsis CDC. Centers for Disease Control and Prevention. https://www. cdc.gov/sepsis/datareports/index.html. Published (update) July 2, 2018. Accessed July 23, 2018