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Tiago Alves Group

Impact of metabolic regulation on cellular function in health and disease

Tiago Alves

© Frank Möller | PLID

The interest in metabolism has been revived in recent years due in part to our evolving understanding of its role in the regulation of cellular homeostasis in a variety of different models and scientific questions. This metabolically driven maintenance of cellular homeostasis is not consistent with the often assumed rigid and linear view of chemical reactions. Rather, it is a highly flexible, interconnected and responsive network that relies on extensive and highly nuanced mechanisms of regulation to direct the flow of metabolites throughout the cell.

Therefore, the general aim of our group is to understand the mechanisms of metabolic regulation in live cells in order to modulate cellular function with targeted metabolic manipulations.

Current projects

  1. Metabolic Fluxes
    We use stable isotopes to the capture the dynamic nature of metabolism. The transfer of mass isotopes, such as 13C, across metabolites is highly specific, well characterized and provides a critical glimpse into the magnitude and direction of individual reactions. Our approach is built upon the previously developed MIMOSA (Mass-Isotopomer Multi-Ordinate Spectral Analysis) method, and is in continuous development as we can expand it to include other pathways or highlight specific reactions depending on the needs of each project. This approach is also used in combination with techniques of computational analysis and molecular biology to extract the most detail possible from each project.
  2. Link between glucose metabolism and insulin secretion/synthesis in beta-cells
    Pancreatic beta-cells are responsible for the secretion of insulin in response to glucose stimulation and represent a major factor in managing and delaying the offset of both Type 1 and Type 2 Diabetes. Our focus here is on understanding the role of metabolism in the regulation of pancreatic beta-cell physiology. We use a combination of metabolic flux screening, computational analysis and genetic manipulation to identify metabolic targets capable of modulating insulin secretion and synthesis.
  3. Role of metabolism in the regulation of stem-cell differentiation
    The transplantation of stem cell generated islets is an approach with great therapeutic potential against the progression of Diabetes. One of the Aldehyde Dehydrogenase isoforms regulates the timing of differentiation and functionality of mature islets. In this project, we aim to understand how this enzyme regulates the interaction between metabolism and the transcriptional and epigenetic machinery responsible for the differentiation program.

Future Projects and Goals

Metabolic regulation is complex and it is continuously updated with novel mechanisms. Our ultimate goal is to combine this knowledge with other disciplines (systems biology, epigenetics, proteomics, etc.) to be in a position to identify which metabolic targets need to be modulated in order to affect a specific function in any cell. We have plans to expand these concepts into other fields such as immune function and cancer physiology. We welcome applicants that share this vision and enthusiasm for metabolism and biochemistry.

Methodological and Technical Expertise

  • Mass Spectrometry
  • 13C-Flux analysis
  • Enzyme kinetics

CV

Since 2020
Group Leader Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD)

Since 2018
Research Group Leader, UKDD, TUD, Germany

2016–2018
Associate Research Scientist, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

2013–2016
PostDoc, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

2012–2013
PostDoc, Department of Anesthesiology and Bioengineering, University of Washington, Seattle, WA, USA

2010–2012
PostDoc, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

Selected Publications

Song JD, Alves TC, Befroy DE, Perry RJ, Mason GF, Zhang XM, Munk A, Zhang Y, Zhang D, Cline GW, Rothman DL, Petersen KF, Shulman GI
Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference
Cell Metab 32(5):726–735.e5. doi: 10.1016/j.cmet.2020.09.008 (2020)

Davis JC, Alves TC, Helman A, Chen JC, Kenty JH, Cardone RL, Liu DR, Kibbey RG, Melton DA
Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis
Cell Rep 31(6):107623. doi: 10.1016/j.celrep.2020.107623 (2020)

Alves TC, Pongratz RL, Zhao X, Yarborough O, Sereda S, Shirihai O, Cline GW, Mason G, Kibbey RG
Integrated, Step-wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle
Cell Metab 22(5):936–47. doi: 10.1016/j.cmet.2015.08.021 (2015)

Petersen KF, Morino K, Alves TC, Kibbey RG, Dufour S, Sono S, Yoo PS, Cline GW, Shulman GI
Effect of aging on muscle mitochondrial substrate utilization in humans
Proc Natl Acad Sci U S A 112(36):11330–4. doi: 10.1073/pnas.1514844112 (2015)

Alves TC, Befroy DE, Kibbey RG, Kahn M, Codella R, Petersen KF, Carvalho RA, Shulman GI
Regulation of Hepatic Fat and Glucose Oxidation in Rats with Lipid-Induced Hepatic Insulin Resistance
Hepatology 53(4):1175–81. doi: 10.1002/hep.24170 (2011)