Marcelo S. Reis

Ongoing projects
In this page we list the main research projects that are currently in execution by our group. If you are interested in working on one of them, either as a student or a collaborator, do not hesitate to contact us!


Development of Bayesian approaches to tackle the lack of isolation problem in signaling pathway
Dynamic models based on ordinary differential equations (ODEs) are useful tools for investigation of cell signaling pathways. Such models allow us to make predictions about the pathway behavior under different stimuli. ODE-based models are often calibrated using experimental data obtained by probing one or more species at several time points after a given cell stimulation. To this end, Bayesian approaches such as the approximate Bayesian computation (ABC) and the extended Kalman filter (EKF) are relevant tools, since they allow the assessment of the uncertainty in the estimation and also are a natural way to carry out model selection. In general, those models are estimated assuming that they are relatively isolated systems with known inputs; however, in many practical situations, we do not have any guarantee that that assumption holds. Therefore, in this project, we propose to tackle the lack of isolation problem in signaling pathway modeling through the development of a new approach based on ABC and/or EKF, which would take into account that model inputs also must be inferred. To this end, we also intend to use the reduction of the model selection problem to the feature selection problem that was recently developed by our group. Finally, we plan to test the new method on artificial instances and also on experimental measurements that are yielded in cancer cells studies at our lab. We expect that the proposed method will become a relevant tool in the studying of cell signaling pathways in many biological contexts, specially in cancer biology studies.

Team

Marcelo S. Reis, PhD - Coordinator

Ronaldo Nogueira - PhD Student

Marcelo Batista - MSc Student

Willian Wang - Undergrad Student

Gustavo Estrela - Former MSc Student, Currently Outside Collaborator

Juliane Liepe, PhD - Associate Investigator
(Group Leader at Quantitative and Systems Biology, Max Planck Institute for Biophysical Chemistry, Germany)

Prof. Hugo A. Armelin - Associate Investigator
(Coordinator of the FAPESP RIDC CeTICS center, Butantan Institute)

Financial Support

This project is currently supported by a PhD scholarship from CAPES. Initial parts of this work were supported by the MSc scholarship # 17/20575-9 from FAPESP, and also by the BPE scholarship # 19/20025-4 from FAPESP; activities of this latter grant were carried out by the Coordinator at Dr. Liepe's group in Göttingen, Germany.

CNPq Research Group

This project is registered at CPNq as the research line "Modelagem de vias de sinalização celular no contexto da biologia do câncer", which in turn is under the research group "Controle do ciclo celular e da diferenciação celular".



Finding the "Goldilocks zones" of cell signaling pathways in cancer therapy
The increase of cancer cell fitness during oncogenesis is accompanied by an increase of several cellular stresses, a phenomenon that may be exacerbated through mitogenic overstimulation. Recently, our group reported an unusual approach to cancer therapy, which relies on mitogenic overstimulation followed by inhibition of stress mitigation pathways. Although mitogenic overstimulation of cancer cells can often be achieved using natural mitogens, which generally are harmless for healthy cells, some types of cancer do not respond well to them. In this case, it might be necessary interventions downstream of mitogenic signaling pathways, a procedure that might also be cytotoxic to healthy cells. Therefore, we hypothesize the existence of a Goldilocks zone, that is, a just right set of such interventions that maximizes treatment efficacy at the same time sparing healthy cells from deleterious effects. To test this hypothesis, we propose to develop a methodology that encompasses: i) a Bayesian model selection procedure that draws candidate models from a reactions database and takes into account the lack of isolation problem that arises during the estimation of signaling pathways models; ii) the designing of classifiers of cell proliferation as a function of signaling pathways dynamics; iii) the incorporation of (i) and (ii) into a combinatorial optimization search for best sets of interventions. To test the proposed methodology, we plan to apply it into synthetic data and on results from experimental assays using cancer and non-tumorigenic cell lines. We also intend to experimentally validate promising predictions obtained with those wet lab assays. Testing this Goldilocks zones hypothesis is a timely endeavor, which could assist the discovery of new mitogenic signaling pathway activators for that novel cancer therapy approach.

Team

Marcelo S. Reis, PhD - Coordinator

Fabio Montoni - PhD Student

Ronaldo Nogueira - PhD Student

Cássia Sampaio - Technical Training Fellow

Marcelo Batista - MSc Student

Vivian Constantino - MSc Student

Anahí Coimbra - Undergrad Student

Willian Wang - Undergrad Student

Juliane Liepe, PhD - Associate Investigator
(Group Leader at Quantitative and Systems Biology, Max Planck Institute for Biophysical Chemistry, Germany)

Prof. Hugo A. Armelin - Associate Investigator
(Coordinator of the FAPESP RIDC CeTICS center, Butantan Institute)

Prof. Junior Barrera - Associate Investigator
(Director of Institute of Mathematics and Statistics, University of São Paulo)

Prof. Ronaldo F. Hashimoto - Associate Investigator
(Associate Professor at Institute of Mathematics and Statistics, University of São Paulo)

Rosangela Wailemann, PhD - Postdoc fellow under Prof. Armelin supervision

Edmilson Ozorio, PhD - Postdoc fellow under Prof. Armelin supervision (Former Member)

Financial Support

This project is currently supported by the Regular Grant # 19/21619-5 from FAPESP, by a PhD scholarship from CAPES and also by the Undergrad Research scholarship # 21/04355-4 from FAPESP.

CNPq Research Group

This project is registered at CPNq as the research line "Modelagem de vias de sinalização celular no contexto da biologia do câncer", which in turn is under the research group "Controle do ciclo celular e da diferenciação celular".


Stochastic models of DNA replication programming in trypanosomatids


Trypanosomatids are protozoan that bear a peculiar genomic topology, with genes organized into polycistrons and constitutive transcription along the whole cell cycle. Given those properties, one hypothesis is that conflicts between DNA replication and transcription machineries contribute for the firing of replication origins along the cell cycle S phase in those organisms. In fact, based on a DNA replication model proposed for human cells, we developed a DNA replication stochastic dynamic model for Trypanosoma brucei that was calibrated with published MFA-seq data and used it to predict that increasing constitutive transcription levels indeed incur in an increase of fired origins; however, such increase has little impact on the overall S phase duration (da Silva et al., 2019). Those predictions were validated experimentally in alpha-amanitin-based transcription inhibition assays (da Silva et al., 2019). Nevertheless, the aforementioned hypothesis was not explored in other trypanosomatids, especially in T. cruzi. Recently, Dr. Maria Carolina Elias' group concluded the DNA origins mapping for T. cruzi through MFA-seq assays. Those assays unveiled that several origins are located in coding regions of the dispersed gene family 1 (DFG-1) genes, a gene family relevant for the parasite life cycle. Once DFG-1 genes have high genetic variability, one possibility is that conflicts between DNA replication and transcription machineries are responsible for the verified genetic variability. If this latter assumption is correct, one corollary is that the origin firing distribution in T. cruzi is conditioned by the parasite's own genomic organization. Therefore, through a combination of dry and wet lab assays, we seek in this project to answer the following questions:

  • Do conflicts between DNA replication and transcription machineries induce increased origin firing in T. cruzi?
  • Is the origin firing distribution in T. cruzi conditioned by the genomic organization?
Apart from the resolution of the aforementioned questions, we aim with this project to improve computational dynamic models of the DNA replication programming. We also expect theoretical advances (e.g., closed solutions of stochastic processes that describe DNA replication dynamics in trypanosomatids), which would be derived through analyses of computational assays.

Team

Marcelo S. Reis, PhD - Coordinator

Bruno Scholl - MSc Student

Ligia Corunha - Undergrad Student

Victor Hariki - Former Undergrad Student, Currently Outside Collaborator

Maria Carolina Elias, PhD - Associate Investigator
(Director of Cell Cycle Laboratory, Butantan Institute)

Marcelo Santos, PhD - Postdoc fellow under Dr. Elias supervision (Former Member)

Gustavo Cayres - Undergrad Student (Former Member)

Financial Support

Initial stages of this project were supported by the Undergrad Research scholarship # 16/17775-3 from FAPESP. Currently, its execution has a financial support from CNPq.

CNPq Research Group

This project is registered at CPNq as the research line "Decifrando a dinâmica de replicação em Trypanosomas", which in turn is under the research group "Controle do ciclo celular e da diferenciação celular".


Archived projects