Role of arachidonic acid derived lipids in angiogenesis and tumorigenesis, tumors, integrins, metalloproteinases, growth factors, diqabetes,
Our laboratory has established two major lines of research.
To study the molecular mechanisms of kidney fibrosis, focusing on cell-matrix interactions and arachidonic acid-derived eicosanoids in kidney injury.
Cell-matrix interaction in kidney homeostasis: As progressive accumulation of extracellular matrix (ECM), mainly collagens, leads to fibrosis, our goal is to determine how interactions between ECM and cells via specific ECM receptors control ECM synthesis/remodeling in health and disease. Among the collagen receptors, we study integrins and discodin domain receptors (DDRs). We have identified integrinalpha1 beta1 as an anti-fibroticintegrin whose activation leads to downregulation of endogenous collagen synthesis and negatively modulates fibrosis. Recently, we have identified integrinalpha2 beta1 and DDR1 as a positive regulator of kidney fibrosis and provide evidence that mice lacking these receptors are protected from fibrosis following injury. Finally, we study how these matrix receptors crosstalk with pro-fibrotic growth factor receptors, including EGF and TGF-b receptors.
Arachidonic acid-derived eicosanoids in kidney homeostasis: The P450 arachidonic acid monooxygenases oxidize arachidonic acid to a) 19- or 20-HETE (w-hydroxylase or CYP4isoforms), or b) 5,6-, 8,9-, 11,12-, or 14,15-EET (epoxygenase or CYP2isoforms). Both EETs and HETEs have markedly divergent biological effects depending on the tissue of origin. For example, 20-HETE causes vasoconstriction and promotes hypertension, while EETs are vasodilators and lower blood pressure. As hypertension and kidney injury are frequently associated, a goal of our research is to determine the relative contribution of EETs vs. HETE to kidney homeostasis by using mice lacking and/or overexpressing key enzymes involved in the synthesis of EETs and/or HETEs. Using these in vivo tools we intend to test the hypothesis that EETs protects from, while 20-HETEs contributes to kidney injury.
To study the molecular mechanisms controlling endothelial cell functions in order to devise valid and better tolerated anti-angiogenic therapy.
In the past 10 years our laboratory has investigated the role of cell-matrix interaction in the control of endothelial cell functions in vivo and in vitro and provide the first evidence that the collagen binding integrin alpha1beta1 is pro-angiogenic and pro-tumorigenic and its inhibition and/or down-regulation is beneficial in the setting of tumor associated angiogenesis. More recently, we have started to investigate the role of arachidonic acid P450epoxygenases in the control of endothelial cell function in vitro and tumorigenesisin vivo. We provide evidence that the products of P450epoxygenases are pro-angiogenicin vivo and in vitro and maneuvers to prevent their synthesis plays a beneficial effect in slowing cancer progression in vivo.