Failure of endogenous regulators of the Toll like receptor pathway...


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Title Failure of endogenous regulators of the Toll like receptor pathway contributes to the pro-inflammatory state and adverse disease outcome in heart failure patients
Period 02 / 2011 - 01 / 2015
Status Current
Dissertation Yes
Research number OND1343951


HF patients are characterized by a persistent inflammatory state. Since inflammatory cytokines contribute to an adverse outcome, anti-inflammatory therapies hold a promise to improve outcome in HF patients. Experimental and observational evidence indicates that the TLR pathway, a highly regulated innate immune system, may be involved in the progression of HF. We obtained pilot data indicating that the immune activation in HF may be due to a failure of negative TLR regulators, controlled by CEBPd, a master protein governing TLR-inflammatory responses. Hypothesis Increased CEBPd suppresses TLR negative regulators, thereby inducing a hyperresponsive immune state in HF patients, which contributes directly to an adverse CV-outcome Specific aims 1) Substantiate the concept that suppressed negative regulators of the TLR pathway are associated with an increased LPS inflammatory response in HF patients. 2) Test the hypothesis that CEBPd downregulates inhibitors of the TLR pathway in HF. 3) Test the hypothesis that IRAK-M and CEBPd modify disease progression in an IRAK-M and subsequently in a CEBPd deficient heart failure mouse model. 4) Test the hypothesis that CEBPd disease progression is dependent on hematopoietic cells. 5) Test the hypothesis that genetic variations in IRAK-M and CEBPd are associated with outcome in HF. 6) Test the hypothesis that prevention of chronic TLR activation by endotoxins reduces CEBPd, normalizes the inhibition by negative regulators of the TLR pathway and dampens the chronically elevated inflammatory state in HF patients

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Supervisor Prof.dr. E.S.G. Stroes
Doctoral/PhD student Drs. D.F. Wijk

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