Research Overview

Our laboratory focuses on molecular mechanisms of septic shock, and septic multiple organ injury (MOI), conditions that claim thousands of life each year. Using modern molecular biology techniques, we are identifying the molecular events that take place when bacterial infections initiate the inflammatory process and lead to the development of septic shock and septic MOI. The purpose of our research is to discover new targets for novel therapies for treating this life-threatening condition. We have recently discovered that in addition to triggering uncontrolled systemic inflammation, bacterial infection also suppresses the expression of multiple “housekeeping genes”, whose products are critical for the maintenance of normal organ functions, and impairs our body’s anti-inflammatory and protective mechanisms. 

We are investigating how bacterial infection represses housekeeping gene expression and impairs the anti-inflammatory and protective mechanisms, and are trying to find the ways of boost these anti-inflammatory and protective mechanisms. Our recent studies have also demonstrated that endothelial-targeted blockade of inflammatory pathways can effectively prevent septic MOI, while avoiding the impairment of our body’s host defense capability, a serious side-effect commonly seen in systemic inhibition of inflammatory pathways. This may lead to the development of novel anti-sepsis therapies.

Research Description

There are 3 on-going research projects in the laboratory. In the first project, we are studying endothelial selective blockade of NF-κB signaling pathway as therapeutic potential in the treatment of septic shock and septic multiple organ injury (MOI) using a murine models of septic shock.  The transcription factor, nuclear factor kappa B (NF-κB) is a major driving force of systemic inflammation. NF-κB activation mediates the expression of hundreds of pro-inflammatory genes, many of their products play an important roles in pathogenesis of septic shock and septic MOI. Studies by our laboratory and others have shown that inhibition of NF-κB activation corrected virtually all major aspects of septic abnormalities. Thus, NF-κB is an ideal target for therapeutic intervention. However, systemic inhibition of NF-κB pathway impairs our host defense mechanisms to fight bacterial infection and causes immune suppression, which are harmful. To develop effective anti-NF-κB therapies, we need to develop alanced approach that attenuates NF-κB-mediated inflammatory and injurious response and also preserves NF-κB-mediated host immune defense response. To this end, we have generated transgenic mice that conditionally over-express mutant I-κBα (I-κBαmt), an inhibitor of NF-κB, selectively on endothelial cells using tetracycline-regulated gene expression system. Utilizing this mouse strain, we have recently demonstrated that endothelial-restricted blockade of NF-κB-driven inflammatory pathways effectively prevented septic MOI, while avoiding the impairment of our body’s host defense capability, a serious side-effect commonly seen in systemic inhibition of inflammatory pathways. This suggests that selective blockade of endothelial NF-κB pathway balances the beneficial and detrimental effects of NF-κB inhibition. We are currently investigating the mechanisms underlying the different effects of endothelial NF-κB inhibition on the two immune responses.

Our second on-going research project investigates how bacterial toxin suppresses or impairs the anti-inflammatory mechanisms and housekeeping gene expression. This project was developed based on our discovery that challenge of mice or rats with LPS in vivo down-regulates the GC box-binding transcription factor, Sp1, activity and diminishes cellular Sp1 protein, which is accompanied by reduced expression of Sp1-dependent housekeeping genes and increased lung microvascular permeability. Because Sp1 regulates the transcriptional expression of hundreds of housekeeping genes, tissue repairing genes as well as multiple anti-inflammatory genes, our finding leads us to propose a novel mechanism that bacterial toxin causes septic shock and septic MOD/I by suppressing the Sp1-mediated housekeeping, anti-inflammatory and tissue repairing mechanisms. We have elucidated the molecular mechanisms underlying the LPS-induced down-regulation f Sp1 activity. We have demonstrated that that LPS down-regulates Sp1 activity by promoting Sp1 dephophorylation and Sp1 protein degradation, and that Sp1 protein degradation is the major mechanism underlying the LPS down-regulation of Sp1 activity. We have further demonstrated that LPS challenge induces a protease activity, which degrades Sp1 protein and down-regulates Sp1 activity. We have identified, characterized and purified the protease that is responsible for LPS-induced Sp1 protein degradation and named it as LPS inducible Sp1 degrading enzyme (LISPDE). We are currently determining the amino acid sequence of LISPDE protein.
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Our third research project investigates the molecular mechanisms through which obstructive sleep apnea (OSA) promotes the development of cardiovascular diseases. OSA is a very common health problem affecting a large portion of the population, and has been recognized as an important risk factor for increased cardiovascular morbidity and mortality. The mechanisms linking OSA with cardiovascular diseases remain largely to be explored. This project was developed based on our initial observation that OSA patients have a markedly elevated neutrophil and monocyte NF-κB activity, and significantly elevated plasma levels of NF-κB-dependent gene products. Our initial observation has stimulated a great interest in this field. Our report has stimulated an editorial and resulted in more than 10 follow up studies worldwide showing that OSA patients have increased plasma levels of markers of systemic inflammation. Because chronic intermittent hypoxia (CIH) is a prominent feature of OSA pathophysiology, we are studying the cardiovascular consequences of exposure to CIH, and studying the mechanisms mediating the CIH effects. We have established a mouse model of CIH. We found that CIH activates NF-κB and that vascular tissue is particularly sensitive to CIH as indicated by increased NF-κB activity and increased expression of NF-κB-dependent gene product. We have also demonstrated that exposure of mice to CIH causes persistent systemic hypertension, increases vascular sensitivity to vasoconstrictor and impairs endothelium-dependent vasodilatation. We are currently investigating the mechanisms mediating CIH induced other cardiovascular dysfunction and pathology. 
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