METABOLISM AND SIGNALING
Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Regulation of endothelial-specific growth factor receptor levels and nucleotide synthesis represent important mechanisms in angiogenic endothelial cells (EC). Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates translation remains elusive. By using genetic, metabolic, and proteomic approaches, we here show that during normal and pathological angiogenesis EC uses a specific metabolic pathway to regulate mTORC1 activation, which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. We anticipate our studies to be a starting point for novel anti-angiogenic approaches based on the inhibition of aminoacid metabolism regulation to overcome anti-VEGF therapies resistance by targeting endothelial growth factor receptor translation machinery.
METABOLISM CONTROL OF CARDIOVASCULAR MATURATION
Vascular mural cells (vMC) play an essential role in the development and maturation of the vasculature by promoting vessel stabilization through their interactions with endothelial cells (EC) in health and in disease. Previous studies have identified a series of endothelial signaling pathways that are critical for mural cell recruitment, differentiation, and vascular stabilization. Whether endothelial metabolism also plays an important role is still unknown. We are investigating the role of endothelial metabolic pathways in vMC coverage of the dorsal aorta (DA) during early vertebrate development.
THE ROLE OF LIPID METABOLISM AND
SIGNALING IN CANCER PROGRESSION
Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Altered lipid metabolism is among the most prominent metabolic alterations in cancer. The role of isoprenoid (mevalonate) lipid metabolism and signaling is left behind. Recent findings indicate that the isoprenoid pathway has several essential outputs in addition to cholesterol, likely important for cancer cell survival. Here we address the role of isoprenoid metabolism in regulating breast cancer and melanoma progression with a particular focus on its regulation of oxidative stress and lipid peroxidation in circulating tumor cells (CTCs).
CIRCADIAN CLOCK IN ANGIOGENESIS
The circadian clock and light-regulated physiological processes play a central role in the regulation of the physiological functions of almost all tissues and organs. Despite the vast knowledge of circadian biology and angiogenesis, the role of the circadian clock in angiogenesis and vascular patterning remains poorly investigated. Here we plan to define mechanistic insight on the role of the circadian clock and light in the regulation of developmental angiogenesis. It is understood that some crucial genes involved in the regulation of cell growth, differentiation, and metabolism are tightly regulated by the clock genes. Such findings may open up new therapeutic approaches in pathological angiogenesis and reasonably extend to other types of vascular-related conditions by targeting the circadian clock.
NOVEL THERAPEUTIC APPROACHES
IN CORNEAL DYSTROPHIES
Dominant mutations in the human UBIAD1 gene lead to a deregulation of free cholesterol and phospholipid metabolism, producing cornea opacification and visual acuity loss, leading to Schnyder Corneal Dystrophy (SCD). The tissue is damaged by high oxidative stress-mediated by iron which leads to lipid peroxidation. UBIAD1 is an enzyme that catalyzes the biosynthesis of CoQ10 or Vitamin K2 and the goal of this project is to unravel such mechanism to provide therapeutic approaches. The plan of the project is based on giving the possibility to repurpose existing FDA-approved drug deferiprone (an iron chelator) and Coq10 for the SCD treatment model and genetically engineered human limbal stem cells will serve for these studies.