Ambra A. Pozzi, PhD
Medical Center North, Room / Suite B-3115, Nashville, TN, TN 37232
Professor of Medicine
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?integrin?alpha1?beta1 as an?anti-fibrotic?integrin?whose activation leads to?downregulation?of endogenous collagen synthesis and negatively modulates fibrosis. Recently, we have identified?integrin?alpha2?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?CYP4?isoforms), or b) 5,6-, 8,9-, 11,12-, or 14,15-EET (epoxygenase or?CYP2?isoforms). 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?P450?epoxygenases?in the control of endothelial cell function in vitro and?tumorigenesis?in vivo. We provide evidence that the products of?P450?epoxygenases?are?pro-angiogenic?in vivo?and?in vitro?and maneuvers to prevent their synthesis plays a beneficial effect in slowing cancer progression?in vivo. ? ? ? ? ? ? ? ? ?
Role of arachidonic acid derived lipids in angiogenesis and tumorigenesis, tumors, integrins, metalloproteinases, growth factors, diqabetes,