Xiaoyo Hu, MD, PhD

Hospital for Special Surgery, New York, NY

2013 Target Identification
2013 Cell Signaling

Hes1 as a Novel Regulator of the Type I Interferon Pathway in SLE

The Study and What It Means to Patients

"Excess amounts of virus-fighting proteins known as interferons drive the lupus immune system's attack on the body. We have discovered a new molecular process in cells that limits how much interferon if produced and are investigating how this natural means of controlling interferon production could be harnessed to treat lupus."

Summary

Blood factors known as interferons are a crucial part of the immune system's defenses against viruses and other microbial invaders. Too much interferon, however, can cause problems such as unwanted activation of the immune system and inflammation that damages organs. In lupus, a flood of excess interferon drives the immune system's misdirected attack on the body's own cells and tissues. We are studying a new sequence of molecular interactions that curbs interferon production - work that might pave the way for novel therapies for lupus that limit interferon production.

Scientific abstract

One of the prominent immunological abnormalities closely associated with SLE is upregulation of type-I interferons (IFNs). Molecular and cellular mechanisms that lead to excessive production of type I IFNs in SLE has been a subject under extensive investigation and the research effort has focused on identifying factors and pathways that positively regulate IFNs expression. On the other hand, given their potential harmful effects, production of type-I IFNs is under tight control by various inhibitory mechanisms that prevent over-activation of this pathway. We postulated that besides abnormal activation of positive IFN-inducing pathways, dysregulation of homeostatic inhibitory mechanisms also contributes to excessive IFN production seen in SLE and identified Hes1 as a previously unappreciated negative regulator of IFN expression. In this application, we propose to investigate the molecular mechanisms by which Hes1 inhibits the type-I IFN pathway as well as the in vivo significance of Hes1 regulation of IFNs in animal models of SLE. The proposed study will contribute to our understanding of IFN regulation in the context of SLE pathogenesis and shed light on designing novel therapeutic approaches targeting type-I IFNs.

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