Università Federico II di Napoli
Aging and disease: coping with oxidation-driven cellular processes
Vittorio Enrico Avvedimento is professor of General Pathology at the Medical School of University "Federico II," Napoli. He received his MD degree at the University of Napoli and completed a residency in Neurology at the School of Neurology of the same University. He spent 2 years, 1978-80, in the laboratory of Molecular Biology, at the National Cancer Institute, NIH, in Bethesda. In 1987 he was awarded the Eleanor Roosevelt Fellowship, ACS. In 2002 he spent the year at the Institute of Cancer Research, Columbia University, as "L. Schaffner" fellow. He is currently coordinator of the PhD program in Molecular Pathology at the University "Federico II," Napoli. This program was ranked in 2007 first among the 120 PhD programs of the University by an independent panel of reviewers.
Avvedimento has been directly involved in the cloning of the first prototypic collagen gene (Cell, 1980, 21, 689-696; Cell, 22, 887-892) and thyroglobulin gene (PNAS, 1986 83, 323-327). By using these molecular tools he dissected a prevalent phenotype in epithelial tumors: the loss of differentiation memory of mammalian cells during neoplastic transformation. The experiments in transformed thyroid cells revealed some general mechanisms governing the transmission of signals by two main transducers, cAMP and Ras. Although these signals were involved in multiple phenotypes, the mechanisms by which they regulated growth and differentiation in mammalian cells were still obscure.
The relevant discoveries can be summarized as follows: 1. Oscillations of the cAMP drive the mitosis in fertilized Xenopus eggs (Science, 1996, 271, 1718-1722). 2. The localization and the type of transducer regulate the timing and the intensity of cAMP nuclear signaling. Neoplastic transformation (Ras) represses differentiation memory by altering the localization of cAMP kinase, PKA (Gen. Dev. 1991, 5, 22-28; 1992, 6, 1621; J.Biol.Chem. 1996, 271, 25350-25359). 3. Somatic mutations of TSH receptor gene drive thyroid hyperfunctioning adenomas (J.Clin. End. Metab., 1994, 79, 657-661).
The information and the tools generated by these discoveries were translated in vivo by inactivating or stimulating specific genes encoding the regulators of these transducers (Ras or cAMP) in several animal models of human diseases--so called somatic gene therapy (Nature Medicine, 1995, 1, 541-545; see also comments and News & Views in the same issue or in Nature, 1995, 375, 433; Nature Medicine, 1996, 2, 634-635; Nature Medicine 1997, 3, 775-779).
In the last 5 years Avvedimento has been focusing his attention on the basic mechanism(s) underlying human diseases. Progressively, during this period, several basic scientific issues, independently approached, are converging on a more comprehensive evolutionary vision. Aging and illness in humans represent a successful compromise between preserving genome stability versus oxidation-driven cellular processes. Oxidation, the basic energy-producing process, is costly, since it continuously attacks DNA and jeopardizes genome stability (New Engl. J. Med (2006) 354 (25): 2667-76). Recent data from the laboratory show that DNA damage and faithful repair are marked by an epigenetic scar (methylation) that silences the surrounding gene(s). This scar, by silencing damaged and repaired genes, represents a powerful evolutionary force, since it preserves the genetic information and reduces further damage to the genome (PLoSGenet. 2007 vol. 3, pp. 1144-1162). At the same time, other data from the lab indicate that oxidation, selective DNA damage and repair drive the basic transcription machinery used by sex hormones (Science 2008 Jan 11;319 (5860): 202-6). How can these two aspects of the same process (genome stability and oxidation) be reconciled? Senescence and diseases may directly derive from the imbalance of oxidation and silencing on gene expression.
While at Columbia, in collaboration with Max E. Gottesman, he will try to answer some of these questions by tracking down some relevant players linking DNA damage to gene silencing and repair.