My research focus has been in the fields of signal transduction pathways, metabolic diseases, pharmacology, and ageing. In particular we have interest in NAD metabolism and non-oxidative roles of NAD (as a signaling molecule). In particular, we explore the non-oxidative roles of NAD in metabolic diseases, and ageing processes. Recently, we have made several key contributions in the field of SIRT1 function and regulation.
Recently we have focused on the modulation of the NAD-dependent deacetylase SIRT1. SIRT1 is an enzyme that is involved in several signaling pathways and appears to be a master regulator of ageing, metabolism and circadian cycle. SIRT1 has also been implicated as the target for the polyphenol resveratrol and may be implicated in the physiological effects of caloric restriction.
We have described for the first time a new crucial enzymatic system, the CD38 pathway, as the main regulator of intracellular NAD levels and SIRT1 activity in vivo. CD38 knockout protects against the development of metabolic syndrome, obesity, and liver steatosis via a NAD/SIRT1 pathway. Now we are exploring this pathway is a possible drug target for the treatment of obesity and metabolic diseases. With this work I have developed considerable expertise in the study of SIRT1, liver metabolism and liver steatosis.
Furthermore, we have developed the tools necessary to pursue an independent, laboratory-based research career in the molecular regulation of SIRT1, liver metabolism, ageing and the biological basis of liver steatosis.
I have developed a solid track record in the area of SIRT1 biochemistry, and physiology as illustrated by being the recent recipient of the Glenn/AFAR Breakthrough in Gerontology award presented by the American Federation for Ageing Research (AFAR) and an RO1 NIDDK grant on this subject.
My laboratory has also recently described the role of the protein DBC1 as an in vivo regulator of SIRT1. We have described that the modulation of SIRT1 by DBC1 is dynamic and is regulated by the metabolic load of the cell. Furthermore, the knockout of DBC1 protects against the development of liver steatosis in mice. We are now exploring the role of SIRT1-DBC1 interaction as a target for small molecule activators of the SIRT1 pathway.
Also my laboratory has interest on the NAD derived second messengers NAADP and cADPR and their roles as regulators of intracellular calcium homeostasis.
We have been the co-discoverers of the molecule NAADP a potent intracellular calcium second messenger that regulates intracellular calcium release in many cell types. Furthermore, NAADP has been implicated in several physiological processes including fertilization, insulin secretion, and myometrial contraction. Recently TPCN2 has been identified as the channel/receptor for NAADP. We have developed a TPCN2 knockout mouse model in our laboratory and continue to explore the role of the NAADP second messenger system in intracellular calcium and on physiological processes including insulin secretion and myometrial contraction.
In addition, we have made multiple and very key contributions in the field of cADPR. cADPR is a cyclic form of ADPR derived from NAD. cADPR is generated by the enzyme CD38 and induces calcium release by opening the ryanodine channel. We have dissected the role of cADPR in calcium release induced by agonists (in particular oxytocin) in human and mouse myometrial cells. The importance of this system for the treatment of preterm and dysfunctional labor is an active line of research in my laboratory. We have also made several very intriguing contributions in the cADPR field including the description of the role of cADPR on the development of toxoplasmosis.
My laboratory has been extremely active and productive on the field of NAD metabolism and the non-oxidative roles of NAD as a signaling molecule. In particular, we have explored the role of NAD dependent deacetylase SIRT1 and its regulation by CD38 and DBC1. Furthermore, we have made crucial contributions in the field of the NAD derived second messengers NAADP and cADPR. We hope to further build in the field of NAD metabolism, sirtuins, CD38, cADPR and NAADP.
One new line of research that is under development in my laboratory is the cellular modulation of the protein acetylome. Recently it has been described that in addition to histones, mitochondrial and cytoplasmic proteins are also acetylated on lysine residues. These acetylations regulate the function of these proteins and have important impact on cellular metabolism. However, how the mitochondrial and the cytoplasmic acetylome are regulated has not been systematically explored to date. Furthermore, the impact of metabolic disease on the global cellular acetylome has not been investigated. With our expertise in the NAD and the sirtuim field we believe that we can make important contributions to the new filed of global protein acetylation and its impact in metabolic diseases (such as obesity, and diabetes) and also during inflammatory conditions (such as sepsis and SIRS).
Our ultimate goal is to understand the metabolic pathways and non-oxidative roles of NAD, providing new avenues for the development of novel and effective pharmacological therapeutic approaches for human diseases such as obesity, metabolic syndrome, ageing related disease, dysfunction, and premature labor.
See my publications
- Professor of Anesthesiology
- Assistant Professor of Medicine
- Resident - Anesthesiology Mayo Graduate School of Medicine, Mayo Clinic College of Medicine
- PhD - Biological Chemistry Universidade do Rio de Janeiro
- Fellow - Department of Physiology and Biophysics Mayo Graduate School, Mayo Clinic College of Medicine
- MD Universidade do Rio de Janeiro
- BS - Biology Centro Educacional de Niteroi-RJ