Research

Chaperokine Activity
At the Division of Investigative Pathology we are focused on furthering our understanding of the chaperokine activity – the heat shock proteins for the development of highly potent and effective heat shock protein-based immunotherapy. Heat shock proteins are highly abundant, stable proteins that possess the special property of binding peptides, small fragments of proteins found inside all cells. This property makes them suited as carrier molecules to sample the peptide antigens found inside cancer cells for use in vaccines to stimulate anti-tumor immunity and enhance immune surveillance.

Fig. 1: Model of stress-induced release of Hsp72

We use cell biology, signal transduction and molecular-immunobiological methods to study heat shock protein responses in a wide variety of diseases. In addition to in-vitro studies, we use pre-clinical animal models to test our working hypothesis (See Fig. 1).

A Leader in Research
Our group was the first to demonstrate that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca2+ flux, activate NF-KappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. More recently, we reported that HSP70-induced pro-inflammatory cytokine production is mediated via the MyD88/IRAK/NF-KappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its pro-inflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis, arteriosclerosis and cardiovascular disease).

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