Our research is focused on cell signaling and how it regulates vascular inflammation, endothelial barrier leakage and breast cancer progression. We employ cell and molecular biology, biochemical and microscopy-based approaches using cell and animal model systems.

Endothelial cells line blood vessels and form a semi-permeable barrier, which is important for maintaining vascular integrity. Endothelial dysfunction contributes to many pathological conditions including cardiovascular disease, cancer and sepsis progression. During vascular inflammation and injury breakdown of the endothelial barrier occurs. We are examining how activation of protease-activated G protein-coupled receptors (PARs) regulates vascular inflammation, endothelial barrier breakdown (pro-inflammatory signaling) and endothelial protection (anti-inflammatory signaling), through selective activation of specific signaling pathways also known as bias signaling. The molecular mechanisms by which ubiquitin and subcellular compartmentalization govern endothelial PAR bias signaling is being actively investigated.
GPCRs are the largest class of signaling receptors in mammalian cells and the largest class of FDA-targets and known to regulate many aspects of cancer pathogenesis. Aberrant GPCR expression and activation has been linked to tumor initiation, progression, invasion and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. The protease-activated GPCR, PAR1 has been implicated in progression of multiple cancers including breast cancer. Signaling by protease-activated GPCRs is tightly regulated through rapid desensitization and endocytic trafficking. We discovered that aberrant PAR1 trafficking results in dysregulated signaling in invasive breast cancer and consequently promotes tumor progression. We are examining how the endocytic machinery and the tumor suppressor ARRDC3 contribute to the dysregulation of PAR1 signaling and the impact on breast carcinoma growth, invasion and metastasis using cell and animal model systems.

 

 

 

The TREJOlab recognizes and appreciates the support from the following sponsors